Biomedical subjects

J A Angus

Publications and source records attributed to J A Angus.

At least 55 records · Page 3Linked to original sources

PubMed1995

omega-Conotoxin GVIA and prazosin, but not felodipine, cause postural hypotension in rabbits.

1. The aim was to compare the effect of N-type calcium channel blockade by omega-conotoxin GVIA (omega-CTX) with alpha 1-adrenoceptor or L-type calcium channel blockade on postural adaptation in conscious rabbits. 2. Orthostatic responses were assessed by rapidly tilting the rabbits through 90 degrees for 1 min. Tilts were performed before, 30 and 60 min after i.v. bolus administration of vehicle (propylene glycol 0.17 mL/kg; n = 8), prazosin (0.5 mg/kg; n = 8), felodipine (30 micrograms/kg; n = 8) or omega-CTX (3 & 7 micrograms/kg; n = 9). 3. Prazosin, felodipine or omega-CTX caused significant falls in mean arterial pressure (MAP) with corresponding increases in heart rate (HR). Vehicle administration had no effect on MAP but caused a small fall in HR. 4. Before drug or vehicle administration, a small rise in MAP and HR occurred in response to tilt in all rabbits. In the vehicle treatment group, similar responses were observed to tilt at 30 and 60 min. Postural hypotension was observed in the prazosin treatment group, but not following administration of felodipine. Tilts 30 and 60 min after omega-CTX (3 micrograms/kg) caused an increase in HR but no change in MAP, different to the small pressor response observed following vehicle administration. However, following administration of omega-CTX 7 micrograms/kg (total dose, 10 micrograms/kg), significant falls in MAP with tachycardia were observed in response to tilt. 5. In conclusion, orthostatic hypotension was observed following acute alpha 1-adrenoceptor or N-type calcium channel blockade in the conscious rabbit. These findings are compatible with the expectation that agents which are directly sympatholytic interfere with postural adaptation. In contrast, L-type calcium channel antagonism with felodipine did not elicit postural hypotension.

Adrenergic alpha-Antagonists↗

PubMed1994

Arteriolar structure and its implications for function in health and disease.

Vascular remodeling is a general term describing any change in blood vessel structure caused by hemodynamic changes, such as flow and pressure, injury, or disease. It also encompasses development and vascularity. This review focuses on the implications of remodeling from both structure and function of isolated arteries and on how a remodeled vascular bed responds to vasoactive stimuli. Essential, genetic, experimental, and pulmonary hypertension, endothelial dysfunction in atheroma, vascular surgery, subarachnoid hemorrhage, congestive heart failure, coronary collateralization, ischemia, and pregnancy are among the examples discussed in this review. Research efforts should be directed toward understanding the processes of cell-cell interaction underpinning these changes in structure and function. Much could be gained from better measurement of vascular structure and full stimulus-reactivity relationships under in vivo conditions in a variety of vascular beds and models of animal and human hypertension. Mathematical models of the average vascular structure drawn from experimental data aid clear thinking when discussing the remodeling process.

Animals↗

PubMed1994

The effects of central administration of omega-conotoxin GVIA on cardiovascular parameters and autonomic reflexes in conscious rabbits.

1. The effects of central administration of omega-conotoxin GVIA (omega-CTX), an N-type calcium channel blocker, were examined in conscious rabbits implanted with lateral intracerebroventricular (i.c.v.) cannulae. 2. Experiments were performed over 4 consecutive days. On day 1, the baroreceptor heart rate (induced by glyceryl trinitrate and phenylephrine) and Bezold-Jarisch like (elicited by serotonin) reflexes were measured before (0 h) and 2 h after central administration of omega-CTX (3 or 30 pmol/kg, i.c.v.) or vehicle. On days 2-4, resting parameters and reflexes were again monitored but no further omega-CTX was administered. 3. No change in heart rate (HR) was observed in any rabbit treatment group during the experimental period. In the vehicle (n = 6) and omega-CTX 3 pmol/kg (n = 6) groups, small falls in mean arterial pressure (MAP) of 6 +/- 2 and 10 +/- 3 mmHg, respectively, occurred between 0 and 24 h; MAP then remained stable. Baroreceptor-heart rate reflex curve parameters did not change in either of these groups during the 4 day period. 4. Following administration of omega-CTX 30 pmol/kg (n = 7), MAP decreased progressively and by 48 h had fallen by 19 +/- 4 mmHg. Also at 48 h, a 20% decrease in HR range of the baroreceptor-heart rate reflex curve was seen without any change in the lower HR plateau from the 0 h control. This indicates that there was an attenuation of the sympathetically mediated upper component of the curve while the vagally mediated component was unaffected.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Evidence for impaired endothelium dependent vasodilation in experimental left ventricular dysfunction.

1. The full range of vascular reactivity was investigated in the hindlimb circulation of conscious, autonomically blocked rabbits with experimental (adriamycin-induced) cardiomyopathy. 2. Adriamycin treatment caused a significant reduction in left ventricular systolic function, as assessed by echocardiography (left ventricular fractional shortening, controls vs adriamycin treatment; 36.7 +/- 1.7% vs 27.3 +/- 2.6%, P < 0.05). 3. Under pharmacological autonomic effector block, the range of the vasodilator response (resistance range, from resting to full vasodilatation) to acetylcholine was reduced by 41% (P < 0.05) and by 37% for adenosine (P < 0.05). Despite these changes the sensitivity (ED50) of the responses were unaltered. 4. The ED50 of constrictor responses to noradrenaline and angiotensin II were similarly unaltered, in conjunction with a non-significant attenuation of the constrictor-response range. 5. These results suggest that in this model of experimental left ventricular dysfunction, the capacity of the hindlimb circulation to respond to regionally infused endothelium dependent vasodilators is attenuated.

Acetylcholine↗

PubMed1994

Effects of dietary marine oil supplementation on reactivity of human buttock subcutaneous arteries and forearm veins in vitro.

1. The vascular reactivity of resistance arteries isolated from gluteal skin biopsies and veins isolated from forearms of subjects fed marine oils were examined. 2. Twenty seven healthy adult males were randomly allocated to one of two different treatment groups. The first group received maxEPA (eicosapentaenoic acid 0.178 g g-1; docosahexaenoic acid 0.116 g g-1) capsules 10 g per day for 28 days while the second group received an equivalent amount of mixed oil placebo capsules. Biopsies were performed on day 29 (13 for gluteal sections; 14 for forearm vein biopsies). Subcutaneous arteries and veins were mounted in myographs and standard organ baths, respectively. 3. The internal diameter of the subcutaneous arteries at a calculated transmural pressure of 100 mmHg averaged 183.7 +/- 10.3 microns in the maxEPA group and 182.6 +/- 19.8 microns in the placebo controls. Arteries from subjects on maxEPA demonstrated increased sensitivity to angiotensin II (maxEPA vs placebo: -log EC50 (M) -8.36 +/- 0.18 vs -7.91 +/- 0.14) but not to noradrenaline or 5-hydroxytryptamine. Concentration-response curves to acetylcholine, substance P and sodium nitroprusside obtained for noradrenaline precontracted vessels were unaltered with marine oil treatment as was the concentration-response curve to calcium in K(+)-depolarized vessels. 4. Vein internal diameter at a calculated transmural pressure of 20 mmHg averaged 3.06 +/- 0.23 mm in the maxEPA group and 2.96 +/- 0.89 in the placebo group. Responses to noradrenaline, 5-hydroxytryptamine, angiotensin II and endothelin-1 were obtained in the absence and presence of indomethacin (1 microM) in veins from both maxEPA and placebo-treated subjects. Neither dietary supplementation with marine oils nor indomethacin had any effect on the responses obtained to these agonists.5. The major finding of the present study was that in general, maxEPA supplementation did not affect responses to various vasoactive substances on isolated subcutaneous arteries or forearm veins. An exception was the observation of an enhanced response to angiotensin II in subcutaneous resistance arteries studied in vitro. This effect was selective for angiotensin II and was not apparent in veins isolated from the forearm.

Adolescent↗

PubMed1994

Pharmacologic dilatation of the internal mammary artery during coronary bypass grafting.

Spasm of the internal mammary artery during coronary bypass grafting is a widely recognized problem during and after mobilization of the IMA. On the basis of previous laboratory studies, we have developed a buffered vasodilator solution containing glyceryl trinitrate and verapamil (pH 7.4). When tested in human internal mammary artery segments in the organ bath, this solution caused full relaxation of the segments with a 1- to 2-minute onset and a duration of action of more than 2 hours. In 31 patients undergoing internal mammary artery grafting, flow through the internal mammary artery was measured immediately after mobilization and 20 minutes later. In 10 untreated patients, flow increased by 13% from 41.8 +/- 7.1 to 47.3 +/- 7.5 ml/min (p < 0.025). In 11 patients, intraluminal injection of glyceryl trinitrate-verapamil solution into the internal mammary artery on one side caused an increase in flow of 55 +/- 10 ml/min (95%), which was greater than that caused by Ringer's solution, 22 +/- 8 ml/min (53%), in the opposite internal mammary artery (p < 0.025). In another 10 patients intraluminal injection of glyceryl trinitrate-verapamil solution in one internal mammary artery caused an increase in flow of 57.9 +/- 8.7 ml/min (107%), which was similar to that caused by papaverine solution (pH 5.2) in the opposite internal mammary artery of 45.0 +/- 12.3 ml/min (80%). We conclude that intraluminal injection of vasodilator solution is effective in dilating the IMA graft and that because of its rapid onset, long action, and neutral pH, glyceryl trinitrate-verapamil solution may be preferable to papaverine.

Coronary Artery Bypass↗

PubMed1993

Pharmacological relaxation of the saphenous vein during harvesting for coronary artery bypass grafting.

Spasm of the saphenous vein frequently occurs during harvesting from the leg and high-pressure distension is required to restore an adequate diameter for grafting. Forceful distention has been shown to damage the intima and media and may predispose to subsequent occlusion of the vein graft. Various pharmacologic vasodilators are capable of relaxing veins; in this study, we carried out a systematic investigation to determine the appropriate agents and concentrations for use during vein graft operations. In organ baths, human saphenous vein segments were contracted with potassium or a thromboxane mimetic, and vasodilator agents were then applied. Glyceryl trinitrate, 7.2 micrograms/mL, or papaverine hydrochloride, 11.9 micrograms/mL, caused 80% to 100% relaxation of contraction induced by potassium or thromboxane. Verapamil, 15.5 micrograms/mL, relaxed the potassium contraction by 100% and the thromboxane contraction by 75%. Comparison of the time course of action showed that glyceryl trinitrate had a rapid onset and a short duration of maximal action, whereas verapamil (like papaverine) had delayed onset and a long duration. A mixture of glyceryl trinitrate and verapamil combined rapid onset with long duration of action. We now use a mixture of glyceryl trinitrate and verapamil (pH 7.4) topically and intraluminally during harvesting of the saphenous vein to provide a relaxed conduit for coronary artery bypass grafting.

Coronary Artery Bypass↗

PubMed1993

Impaired contraction and relaxation in skin resistance arteries from patients with congestive heart failure.

OBJECTIVE: The aim was to determine the pharmacological reactivity of human small resistance arteries in patients with cardiac failure. METHODS: Small arteries (< 300 microns internal diameter) were removed from gluteal skin biopsy specimens and mounted in a double myograph for isometric force recording. RESULTS: Arteries from six patients with congestive heart failure contracted to only 65% of the maximum response recorded in nine arteries from normal volunteers when activated by potassium chloride (124 mM), noradrenaline (1 microM), or both. The lesser contraction in congestive heart failure vessels with no significant shift in sensitivity (EC50) was also observed in concentration-response studies with noradrenaline, angiotensin I, and angiotensin II. The concentration-contraction curves for serotonin showed only 40% of the maximum contractility to K+ in normal arteries, and this ratio was similar in congestive heart failure arteries. Normal arteries precontracted with noradrenaline (1 microM) relaxed in response to sodium nitroprusside, calcitonin gene related peptide, and the endothelium dependent agonist acetylcholine; in congestive heart failure vessels there was a marked loss of the relaxation response only to acetylcholine. CONCLUSIONS: These results suggest that in chronic congestive heart failure skin resistance arteries have impaired contraction responses probably independent of any receptor down regulation. The loss of endothelium dependent vasodilatation to acetylcholine suggests that EDRF release is impaired. These changes may well play an important role in the disturbances of peripheral vascular function associated with heart failure.

Aged↗

PubMed1993

Acute and chronic inhibition of nitric oxide synthase in conscious rabbits: role of nitric oxide in the control of vascular tone.

Acute and chronic effects of Nw-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide synthase, were examined on the hindquarter hemodynamics of conscious rabbits. After pharmacological autonomic reflex blockade on four experimental days (days 0, 1, 2, and 7), responses to aortic occlusion (balloon cuff, 5-80 s inflation), intra-aortic infusion of acetylcholine, adenosine, and sodium nitroprusside (SNP) were measured before and after vehicle (day 0) or L-NNA (16 mg/kg/h i.v., days 1, 2, and 7). On day 1, L-NNA raised the mean arterial pressure (MAP), and lowered the heart rate (HR) and hindquarter vascular conductance (HVC = abdominal aortic Doppler blood flow/MAP). On days 2 and 7, L-NNA only slowly raised the MAP. The dilator response to acetylcholine was inhibited by L-NNA on day 1 and before and after L-NNA on days 2 and 7. The responses to aortic occlusion, adenosine, or SNP infusion were unaffected by L-NNA treatment on any day. Thus, if nitric oxide synthase inhibition by L-NNA abolishes NO release, then (i) reactive hyperaemia is independent of NO, (ii) basal NO release normalises the arterial pressure in the short term but other factors become important in the long term, and (iii) the blockade by L-NNA of receptor-stimulated NO release by acetylcholine is only very slowly reversible.

Acetylcholine↗

PubMed1993

Comparison of contractile responses to 5-hydroxytryptamine and sumatriptan in human isolated coronary artery: synergy with the thromboxane A2-receptor agonist, U46619.

1. The interaction between the thromboxane A2 receptor agonist, U46619 and two 5-hydroxytryptamine (5-HT) receptor agonists, the non-selective, naturally occurring agonist, 5-HT and the selective 5-HT1-like agonist, sumatriptan were studied in human epicardial coronary arteries in vitro. 2. Coronary artery rings (2-4 mm in diameter) were prepared from epicardial arteries from explant hearts of patients undergoing heart transplant (cardiomyopathy, n = 13; ischaemic heart disease, n = 10) and unused donor hearts (n = 5). Each ring of artery was set at optimal resting conditions to record changes in isometric force. 3. The majority of artery rings developed phasic, rhythmic contractions either spontaneously or in response to all vasoconstrictor agonists tested. Both the spontaneous and agonist-induced phasic contractions were abolished by nifedipine (0.1 microM). 4. Concentration-contraction curves to 5-HT-receptor agonists and noradrenaline (NA), were first constructed in artery rings that did not develop phasic activity. 5-HT and ergometrine were the most potent agonists with EC50 values of 6.8 +/- 0.2 and 7.7 +/- 0.2 (-log M) respectively. Potencies (EC50's) to sumatriptan, methysergide and noradrenaline could not be determined due to their poor ability to contract the coronary artery. Maximum contractions (Emax; normalized as a percentage of the contraction to a maximum-depolarizing concentration of K+ in physiological salt solution (KPSS)) for 5-HT, ergometrine, sumatriptan, methysergide and noradrenaline were 40 +/- 10, 9 +/- 3, < 5, < 5 and < 5% respectively. 5. In arteries without phasic activity, U46619 (1 nM) caused an increase in force of 3.8 +/- 1% KPSS. With U46619 present, the Emax values for 5-HT, ergometrine, sumatriptan and methysergide were all markedly increased. For 5-HT and sumatriptan, E., values were 92+/- 4% and 49 +/- 14% KPSSrespectively. The presence of U46619 did not significantly change the sensitivity (EC50) to 5-HT.6. In a separate series of arteries, nifedipine (0.1 microM) was used to block phasic, contractile activity. The synergy observed between U46619 and 5-HT or sumatriptan still occurred although the Emax values for each agonist were depressed but the EC50 values were again unaffected.7. In conclusion, these in vitro studies indicate that the normally poor contractions to sumatriptan, inhuman coronary arteries are significantly enhanced when active force is induced with a thromboxane A2-receptor agonist, U46619. The enhanced response is not specific for either sumatriptan or 5-HT,-like receptors since contractions to 5-HT, ergometrine and methysergide were also potentiated by U46619.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

Evidence that 5-HT2 receptors predominantly mediate the contraction of the rat basilar artery to 5-hydroxytryptamine.

We characterised the 5-hydroxytryptamine (5-HT) receptor subtype which mediates the contraction of the rat isolated basilar artery, mounted in a myograph, by using agonists and antagonists for 5-HT1-like, 5-HT2, 5-HT3 and 5-HT4 receptors. The rank order of potency for a range of selective agonists was: 5-HT > alpha-methyl-5-HT > 5-carboxamidotryptamine > 2-methyl-5-HT > sumatriptan. The maximum contractions for these agonists (Emax) was less than for 5-HT while 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) was devoid of contractile activity. Ketanserin antagonised the contractile effect of 5-HT in the rat basilar artery with a provisional pA2 estimate of 9.3 +/- 0.2. A similar antagonism was observed against alpha-methyl-5-HT. Ergometrine (0.01-1 microM) was devoid of any agonist activity but antagonised the contractile effect of 5-HT on the rat basilar artery with a provisional pKB of 8.7 (7.8-9.8, 95% confidence limits). The 5-HT3 and 5-HT4 receptor antagonist ICS 205930 (10 microM) did not alter the response to 5-HT. The high potency and efficacy of alpha-methyl-5-HT, poor effect of sumatriptan and antagonism of 5-HT by ergometrine and ketanserin, support the conclusion that the 5-HT2 receptors are primarily responsible for the 5-HT-induced contraction of rat basilar artery.

Animals↗

PubMed1992

Symbiotic relationship between a research institute and a pharmaceutical company: the Baker Institute/Glaxo Australia story.

1. The Baker Medical Research Institute is a non-profit, charitable institution to advance knowledge and solve problems in the area of cardiovascular medicine. This allows scientists to collaborate within a critical mass and be flexible in their approach to research. 2. The Institute has interactions with the pharmaceutical industry at three levels: (i) contract research on a specific molecule; (ii) clinical trials; and (iii) collaborative basic research agreements. 3. The Glaxo Australia-Baker Medical Research Institute Agreement is for curiosity driven research in specified areas of vascular pharmacology of interest to Glaxo Group Research. 4. The relationship between universities, research institutes and the pharmaceutical industry is discussed in terms of the starting point for drug development. 5. The enormous cost (US$100 million), lead time (10 years) and uncertainty of a successful profitable drug are compelling reasons why an independent pharmaceutical company is unlikely to succeed in Australia today.

Academies and Institutes↗

PubMed1992

Enhanced contraction to noradrenaline, serotonin and nerve stimulation but normal endothelium-derived relaxing factor response in skin small arteries in human primary hypertension.

1. We measured the reactivity of 2 mm long ring segments of human resistance arteries dissected from gluteal skin biopsies and mounted on wires in a Mulvany-Halpern myograph for recording isometric force. Arteries were taken from eight normotensive (N) volunteers (average age 46 years, blood pressure 126/82 mmHg) and eight untreated hypertensives (H; average age 48 years, blood pressure 149/101 mmHg). 2. In small diameter arteries (internal diameter less than 500 microns), the cumulative concentration-response curves to noradrenaline, serotonin and angiotensin II had a greater maximum by 72, 300 and 69%, respectively, in vessels from hypertensive patients than in those from normal volunteers. Nerve stimulation also caused a greater maximum contraction in hypertensive vessels (by 352%). 3. Arteries from H and N patients contracted submaximally by the thromboxane mimetic U46619 were similarly sensitive to the endothelium-dependent relaxing factor (EDRF) acetylcholine, indicating no difference in EDRF release or sensitivity. 4. Morphological measurements of the ratio of wall thickness to lumen radius of the wire-mounted vessels showed no significant difference between H and N vessels. 5. In larger arteries (internal diameter greater than 500 microns), no response to acetylcholine was noted in either H or N arteries. The sensitivity to serotonin and angiotensin II was similar between these arteries but the EC50 to noradrenaline was less in H than in N arteries (delta EC50 = 0.61 -log mol/L). 6. Subcutaneous resistance arteries with an internal diameter less than 500 microns from hypertensive patients show enhanced contractility to noradrenaline, serotonin and nerve stimulation despite a lack of detectable medial hypertrophy.(ABSTRACT TRUNCATED AT 250 WORDS)

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

Interpretation of the acetylcholine test of endothelial cell dysfunction in hypertension.

BACKGROUND: In the hypertensive circulation, endothelial cells may release less nitric oxide or more endothelin-1, both powerful vasoactive substances, suggesting an attractive hypothesis for the initiation or reinforcement of hypertension. These substances, however, are not the only way that endothelial dysfunction could be involved in hypertension. In this work we examine the role of the endothelium as a diffusion barrier to vasoconstrictor substances, as a metabolic barrier and as a secretory source of paracrine hormones. REVIEW OF DATA: The evidence that endothelial cell dysfunction occurs in different forms of hypertension comes mainly from the loss of relaxation revealed by the 'acetylcholine test' in a variety of preparations. We examined the strength of this evidence in terms of the stability of the agonist, equilibrium between agonist and receptor, and variations in acetylcholine and other receptor populations on endothelial and smooth muscle cells. The range (Emax) and sensitivity (EC50) of the acetylcholine test was considered in a novel approach to determine the full range by in vitro assay. Using conscious rabbits, we showed that the vascular amplifier of resistance in the hypertensive bed can lead to misinterpretation of changes in reactivity. CONCLUSION: The question of endothelial dysfunction in hypertension as determined by the acetylcholine test is far from proven.

Acetylcholine↗

PubMed1992

Release of endothelium-derived relaxing factor from resistance arteries in hypertension.

Aortic rings from SHR are reported to have a decreased relaxation response to the endothelium-dependent agent acetylcholine compared with rings from WKY rats. Thus, a reduced EDRF (nitric oxide) response could contribute to hypertension. We found that in mesenteric small resistance arteries (200 microns I.D.) taken from 5- to 50-week old rats and mounted in a Mulvany-Halpern myograph, that the concentration-response curves to acetylcholine were similar in range and sensitivity (EC50) in arteries from SHR and WKY rats at the same age. Similarly, in small resistance arteries from human buttock skin, the relaxation to acetylcholine was not different between vessels from normotensive volunteers (mean BP = 95.2 +/- 1.5 mm Hg) and patients with untreated essential hypertension (mean BP = 116.5 +/- 2.5 mm Hg). In rabbits with chronic renovascular hypertension (cellophane renal wrap), acetylcholine and adenosine infusions into the lower abdominal aorta caused falls in hindquarter resistance that were enhanced in range, but with no change in sensitivity compared with normotensive rabbits. In normotensive rabbits, nitric oxide synthase inhibition with N omega-nitro-L-arginine infusion caused a rise in blood pressure, fall in hindquarter conductance and blockade of the acetylcholine responses. These experiments suggest that at the level of resistance arteries in vivo and in vitro, a defect in the receptor-stimulated response to EDRF associated with hypertension could not be detected. Apparently, basal nitric oxide is important in resting vasodilator tone, but its role in chronic hypertension is still unclear.

Acetylcholine↗

PubMed1992

Relationship between the sympatholytic action of nebivolol and hypotension.

Nebivolol, a chemically novel beta 1-adrenoceptor antagonist, acutely lowers blood pressure in spontaneously hypertensive rats, anaesthetised normotensive dogs, and hypertensive patients. We have investigated the actions of dl-nebivolol in five conscious normotensive rabbits (sham, mean blood pressure (BP) of 82.2 +/- 4.1 mm Hg, mean +/- SEM) and four hypertensive rabbits (renal wrap hypertension) (wrap, mean BP of 117.6 +/- 1.5 mm Hg). Nebivolol (1 mg/kg i.v.) did not significantly lower the BP or heart rate in either group 30 min after injection. In the same rabbits, on another day, after autonomic blockade (mecamylamine), nebivolol (0.1, 0.3, and 1.0 mg/kg i.v.) right shifted the bolus i.v. isoproterenol tachycardia dose-response curves by dose ratios of 5, 18, and 90 in sham rabbits, respectively, and 5, 11, and 23 in wrap rabbits, respectively, indicating significant cardiac beta 1-adrenoceptor antagonism. In guinea pig isolated right atria pretreated with atropine (1 microM) and desipramine (DMI, 0.1 microM), norepinephrine concentration-response curves were antagonised competitively by nebivolol (3-100 nM), giving a pKb of 7.90. In separate atria without DMI pretreatment, neither nebivolol (100 nM) nor propranolol (100 nM) had any significant effect on the increase in the rate of norepinephrine efflux following electrical field stimulation (0.5-2 Hz, 3 min). These findings suggest that at concentrations of nebivolol that show substantial beta 1-adrenoceptor antagonism, there is no evidence of hypotension or bradycardia nor additional effects on cardiac norepinephrine release. Why nebivolol lowers blood pressure in some species but not in the conscious rabbit is not known.

Adrenergic beta-Antagonists↗

PubMed1991

Oxyhaemoglobin increases the production of endothelin-1 by endothelial cells in culture.

Cultured endothelial cells from bovine thoracic aortas conditioned with serum-free culture media released an endothelin-1 (ET)-1-like substance. Concentrations of ET-1-like material were determined by bioassay as contractions of isolated ring segments of dog internal mammary vein and by radioimmunoassay. ET-1-like immunoreactivity (ET-1-IR) increased progressively over a 24 h conditioning period and correlated with the bioassay for the first 12 h. Oxyhaemoglobin (1-3 microM) caused a significant two-fold increase in the concentration of ET-1-IR in the medium at 6, 8 and 12 h incubation. Methaemoglobin also caused an approximate doubling of the amount of ET-1-IR at eight h of incubation. NG-Monomethyl-L-arginine (L-NMMA), a blocker of the production of endothelium-derived relaxing factor (EDRF), had no effect on the time-dependent increase in ET-1-IR in the conditioned medium. These results may have important implications for the mechanisms underlying vascular smooth muscle hyperreactivity such as cerebral spasm following subarachnoid haemorrhage.

Animals↗

PubMed1991

Experience with calcium antagonists nitrendipine, diltiazem, and verapamil and beta 2-agonist salbutamol in salvaging ischemic skin flaps in rabbits.

This study investigated the efficacy of selected agents in the salvage of experimental skin flaps in rabbits after 21 hours of 25 degrees C ischemia. Calcium channel antagonists nitrendipine, diltiazem, and verapamil increased ischemic skin flap survival in rabbits from 33.3% for buffered saline infused controls to 71.4% (P less than 0.05), 71.4% (P less than 0.05), and 50.0% (not significant) respectively. The beta 2-adrenoceptor agonist salbutamol produced an increase in survival to 64.3%, which narrowly missed statistical significance. All four test agents invoked a vasodilatory response (greatest for nitrendipine, diltiazem, and salbutamol), a slight fall in blood pressure, and a small increase in heart rate. It is concluded that the vasodilatory response in the microcirculation of the ischemic flap helped to minimize the risk of occlusion due to thrombosis or cell sludging during reperfusion, thus leading to improved flap survival.

Albuterol↗