Biomedical subjects

J A Angus

Publications and source records attributed to J A Angus.

At least 73 records · Page 4Linked to original sources

PubMed1991

Spasmolytic effect of cromakalim in dog coronary artery in vitro.

Isometric force development was measured in isolated ring segments of dog left anterior descending coronary artery to K+ (10-70 mM), U-46619 (0.3-30 nM), endothelin-1 (0.1-30 nM), 5-HT (0.1-30 microM) and angiotensin-II (0.1-30 nM). Compared with the maximum tissue response to a K+ depolarizing solution (100%) there was a marked variation in the maximum response to each spasmogen: K+ (111%), U-46619 (85%), endothelin-1 (48%), 5-HT (49%) and angiotensin-II (15%). In arteries pretreated with cromakalim (0.3 - 10 microM) the maximum response to all constrictor agents (with the exception of K+) was reduced but the potency was unaffected. Maximum responses to angiotensin-II and 5-HT were affected at concentrations approximately threefold lower than those to endothelin-1 and U-46619. Removal of the endothelium increased the maximum response caused by 5-HT and reduced the potency of cromakalim in inhibiting this contraction. Glyceryl trinitrate and sodium nitroprusside were 100-1000 times more potent than cromakalim although they produced qualitatively similar effects. Cromakalim is an effective spasmolytic against a number of vasoconstrictors in the dog coronary artery. No marked spasmogen selectivity could be identified for cromakalim that was not shown by glyceryl trinitrate or sodium nitroprusside.

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

PubMed1991

Prostacyclin and prostanoid modifiers aid ischemic skin flap survival.

Prostacyclin, the stable prostacyclin analogue carbacyclin, the thromboxane synthetase inhibitor UK-38,485, and the phosphodiesterase inhibitor dipyridamole were tested on rabbit epigastric free flaps for their ability to improve flap survival after a period of ischemia. Control flaps infused with a balanced salt solution had a 39.9% survival, whereas prostacyclin, carbacyclin, and dipyridamole significantly increased flap survival to 68.4% (P less than 0.05), 66.4% (P less than 0.05), and 66.9% (P less than 0.05), respectively. UK-38,485 improved survival slightly to 47.6% although not significantly. The improved flap survival correlated with the vasodilatory properties of the three successful agents whereas the antithrombotic properties of UK-38,485 were not sufficient, on their own, to increase flap survival.

Animals↗

PubMed1991

Amplifier function of resistance vessels and the left ventricle in hypertension.

We have recently modeled the structural factors responsible for the increased slope of the dose-vascular resistance response curves in the hindquarter bed under both in vitro and in vivo conditions. Slope increases when the ratio of wall thickness to internal radius (ri) increases and when ri decreases, but the slope decreases with greater wall stiffness. Enhanced slope is an indicator of the vascular amplifier properties. Resistance at maximum vasodilation in hypertension is also structurally determined converting enzyme inhibitors in spontaneously hypertensive rats (SHR) suggest that the reduction in ri can be reversed, suggesting that it is due to vascular hypertrophy. The concentrically hypertrophied left ventricle is an amplifier of stroke volume. Together, the vascular and left ventricular amplifiers contribute about 70% to the elevated total peripheral resistance in renovascular hypertension. In SHR, the vascular amplifier is present early in postnatal life before the onset of hypertension, which occurs in parallel with left ventricular hypertrophy (LVH). The development of the vascular amplifiers appears to be under the control of the renin-angiotensin system, whilst LVH appears to be under sympathoadrenal control, acting through cardiac alpha-adrenoceptors. Early immunosympathectomy plus prazosin treatment specifically prevents development of LVH in SHR and also prevents hypertension. In human hypertension, cardiac hypertrophy also plays an important role; after a period of prolonged therapy, the rate of redevelopment of hypertension when the drugs are stopped depends on the degree of regression of LVH during treatment. We conclude that the early development of vascular and cardiac amplifiers in primary hypertension appears to be genetically determined and the role of the heart in pathogenesis appears to be greater than previously thought.

Animals↗

PubMed1991

Significance of cardiovascular hypertrophy in the development and maintenance of hypertension.

The amplifier properties associated with the structural changes in the heart and resistance vessels in chronic hypertension together play a major role in maintaining the elevated blood pressure (BP) in chronic hypertension, which is greater than that of the initiating cause. In patients with primary hypertension, long-term antihypertensive drug therapy causes substantial regression of the structural changes, as assessed by normalization of the total peripheral resistance (including the nonautonomic component) and of the left ventricular (LV) mass. Reversal of LV hypertrophy (LVH) took considerably longer than reversal of the vascular changes and the more complete the reversal of LVH, the slower the rate of redevelopment of hypertension upon cessation of treatment. We observed no change in sympathetic activity or in renin-angiotensin-aldosterone levels during the redevelopment phase and we hypothesized that the cardiovascular amplifiers played a role in pathogenesis. This hypothesis was examined in spontaneously hypertensive rats (SHRs), where the vascular amplifier properties were developed substantially by 4 weeks of age, i.e., before the development of hypertension, whereas LVH occurred pari passu the rise in BP. When young SHRs were treated with enalapril for brief periods, there was almost complete long-term regression of vascular amplifier properties, but attenuation of LVH and hypertension were both smaller and more transient. In 4-week-old SHRs, complete abolition of sympathetic activity had a minimal effect on vascular amplifier properties, but affected LVH. Our findings suggest that LVH is as important in both the development and maintenance of hypertension as the structurally determined amplifier properties of the resistance vessels.

Animals↗

PubMed1991

The acetylcholine paradox: a constrictor of human small coronary arteries even in the presence of endothelium.

1. In animal experiments, acetylcholine is generally a vasodilator acting indirectly by releasing endothelium-derived relaxing factor (EDRF); for example, in dog and rabbit small coronaries mounted in a myograph, acetylcholine caused concentration-dependent relaxation. 2. In human small coronary arteries taken from the atrial appendage, however, acetylcholine caused concentration-dependent contraction with a functionally intact endothelium as shown by the relaxation in response to substance P, another stimulant of EDRF release. 3. We propose that coronary microvessels from various species have variable populations of acetylcholine receptors on the medial smooth muscle that cause contraction and on the endothelium that cause the release of EDRF. In humans, the medial smooth muscle receptors appear to predominate, and may thus play a role in coronary vasoconstriction.

Acetylcholine↗

PubMed1991

Evidence for a role for the cardiovascular amplifiers in human primary hypertension.

1. Hypertrophy of vascular and cardiac smooth muscle is present in human primary hypertension. The amplifier properties associated with hypertrophy play a major role in maintaining hypertension. 2. Long-term antihypertensive drug therapy causes substantial regression of the structural changes, assessed by the non-autonomic component of vascular resistance, and by left ventricular mass. The latter occurs more slowly. 3. The more complete the reversal of left ventricular hypertrophy, the more slowly hypertension redevelops if long-term antihypertensive therapy is discontinued. 4. Subjects who redevelop hypertension more rapidly tend to have higher cardiac output, suggesting that the cardiac amplifier may play a role in the pathogenesis. 5. Studies of small arteries and of veins from patients with primary hypertension suggest that there may be a general disturbance of vascular smooth muscle function, independent of the mechanical effects of elevated systemic blood pressure.

Antihypertensive Agents↗

PubMed1991

Evidence that acetylcholine-mediated hyperpolarization of the rat small mesenteric artery does not involve the K+ channel opened by cromakalim.

1. Acetylcholine causes a concentration-dependent hyperpolarization of the rat small mesenteric artery (diameter at 100 mmHg, 200-400 microns). In the absence of tone the average potential change was from approximately -60 to -75 mV. In the presence of tone induced by endothelin-1 (20 nM), acetylcholine caused vasorelaxation in association with a marked hyperpolarization; from approximately -32 to -71 mV. 2. A number of compounds known to antagonize the actions of cromakalim were tested for their ability to block responses to acetylcholine. Glibenclamide (0.1-3 microM), phentolamine (10-100 microM) and alinidine (1-30 microM) caused a concentration-dependent depolarization of the rat small mesenteric artery which was not dependent on an intact endothelium. Glibenclamide was approximately 10 times more potent than either phentolamine or alinidine, a similar ratio to their potency as antagonists of cromakalim. 3. In the presence of concentrations of the cromakalim antagonists which functionally inhibited responses to cromakalim, only phentolamine and alinidine had a significant effect on the hyperpolarization and functional responses to acetylcholine. Glibenclamide was without effect at the concentrations used. 4. Experiments on pig coronary artery, where acetylcholine causes vasoconstrictor responses, showed that phentolamine and alinidine have some anti-muscarinic activity which could account for their ability to affect vasorelaxant/hyperpolarization responses to acetylcholine in the rat small mesenteric artery. 5. The results suggest that the acetylcholine-mediated hyperpolarization observed in the rat small mesenteric artery does not involve K+ channels opened by cromakalim. This finding differs from other studies performed on the rabbit middle cerebral artery which show hyperpolarizing responses to acetycholine to be glibenclamide-sensitive. It is likely therefore that the hyperpolarization response observed to acetylcholine can be initiated through a number of mechanisms, only one of which utilizes K+ channels opened by cromakalim.

Acetylcholine↗

PubMed1991

Central sympathoinhibition and peripheral neuronal uptake blockade after desipramine in rabbits.

Peripheral- and central nervous system (CNS)-mediated effects of desipramine (Des) on sympathetic nerves and the contribution of alpha 2-adrenoceptors to these effects were studied in conscious rabbits. Blood pressure, renal sympathetic nerve activity (SNA), and norepinephrine (NE) reuptake and spillover into plasma were measured before and after intracisternal (ic) or intravenous (i.v.) administration of Des. In other animals, NE spillover responses to i.v. Des were examined before and after alpha 2-adrenoceptor blockade with i.v. idazoxan. Treatment with i.v. Des blocked neuronal reuptake and decreased renal SNA but did not alter blood pressure or NE spillover. Decreased NE release by sympathetic nerves after i.v. Des was reflected by a decrease in the combined rate of NE reuptake and spillover. Treatment with ic Des (at 1.7% of the i.v. dose) decreased blood pressure and renal SNA and produced equivalent falls in NE reuptake and spillover, indicating little peripheral effect of centrally administered Des on the efficiency of neuronal reuptake. Thus Des had two distinct actions: the drug blocked neuronal reuptake by direct actions on nerve endings and reduced SNA by actions within the CNS. After ic Des, decreased SNA produced parallel falls in NE reuptake, spillover, and blood pressure. After i.v. Des, blockade of neurotransmitter reuptake increased NE concentrations at sympathoeffector junctions offsetting the fall in SNA, so that there was little change in NE spillover or blood pressure. However, after alpha 2-adrenoceptor blockade with i.v. idazoxan, NE spillover increased in response to i.v. Des. Thus the Des-induced decrease in NE release was partly mediated by an action of raised intrasynaptic NE concentrations on inhibitory alpha 2-adrenoceptors.

Adrenergic alpha-Antagonists↗

PubMed1991

Reactivity of canine isolated epicardial collateral coronary arteries. Relation to vessel structure.

To study the relation between structure and vascular reactivity in mature coronary collateral arteries, we prepared 17 dogs with a casein occluder near the origin of the circumflex coronary artery. At least 24 weeks later, we examined the reactivity of surface collateral arteries (approximately 500 micron i.d.) to a range of constrictor and dilator agents and compared them with normal left anterior descending coronary arteries of similar size branching away from the collateral zone. Pairs of normal and collateral arteries 2 mm long were mounted in a double-vessel myograph for isometric force recording. Arteries were contracted by K+ (124 mM) or by cumulative addition of endothelin-1 (1-100 nM) or U46619 (1-300 nM), a thromboxane A2 mimetic drug. In each case, the collateral vessels contracted to approximately half the force generated by the normal arteries. When partially contracted by K+ (25-30 mM), the collateral vessels had a greater range of relaxation and similar sensitivity to acetylcholine, sodium nitroprusside, and cromakalim compared with normal arteries. Morphological and morphometric analyses revealed that the collateral arteries had thickened adventitia, thinner media, ruptured internal elastic laminae, and a thick neointima lined by endothelium. Theoretical calculations of luminal area were made for isotonic conditions in response to constrictor stimuli. Despite the poor contractility of the collateral arteries, the neointimal luminal encroachment further reduced the lumen to zero, an exaggerated response compared with normal arteries. Coronary collateral arteries are thus compromised flow conduits that may play a role in vasospastic angina.

Animals↗

PubMed1990

Apparent vascular to cardiac sympatholytic selectivity of omega-conotoxin GVIA in the pithed rat.

The effects of omega-conotoxin GVIA (omega-CTX), a blocker of N-type voltage-operated calcium channels (VOCCs), were investigated in the pithed rat, omega-CTX (1.6 and 3.2 micrograms/kg i.v.) did not alter resting diastolic pressure or heart rate nor the pressor and chronotropic responses to noradrenaline injections (0.1-10 micrograms/kg). In contrast, the pressor responses to electrical stimulation of the whole spinal cord (0.2-6.4 Hz) were dose dependently reduced by omega-CTX whereas the concomitant tachycardia was less affected. When selective stimulation of the cardiac sympathetic outflow was applied, the resulting chronotropic response was more sensitive to omega-CTX. This result is discussed in the light of the possible interference of adrenal catecholamine release during whole spinal cord stimulation which is not sensitive to omega-CTX. These results provide in vivo evidence that omega-CTX is able to reduce sympathetic neurotransmission to the vasculature and the heart, presumably by blocking N-type VOCCs on pre- and post-ganglionic nerve terminals.

Animals↗

PubMed1990

Simultaneous determination of plasma noradrenaline and adrenaline kinetics. Responses to nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia in the rabbit.

Liquid chromatographic fractionation and detection of exogenous radiolabelled and endogenous catechols was used to examine simultaneously the plasma kinetics of noradrenaline and adrenaline in the conscious rabbit. Plasma clearances and release of noradrenaline and adrenaline into plasma were compared before and during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia, stimuli purported to differentially affect catecholamine release from sympathetic neurons and the adrenal medulla. Plasma concentrations of dihydroxyphenylglycol (DHPG) were also measured to assess presynaptic sympathetic function. Plasma clearances of adrenaline correlated with, but were significantly less than those of noradrenaline. Plasma clearances of both catecholamines showed significant decreases during nitroprusside-induced hypotension and 2-deoxyglucose-induced glucopenia. Glucopenia and hypotension increased the release into plasma of noradrenaline and adrenaline, but the adrenaline response relative to the noradrenaline response was greater during glucopenia than during hypotension. Plasma DHPG concentrations increased during glucopenia and hypotension, consistent with increased neuronal reuptake of noradrenaline and therefore a neuronal source--as opposed to an adrenal source--of most of the noradrenaline appearing in plasma during the stimuli. The increase in plasma DHPG relative to that of noradrenaline was greater after 2-deoxyglucose than after nitroprusside suggesting that the presynaptic handling of noradrenaline during glucopenia was different from that during hypotension or that the two stimuli released DHPG from regionally distinct sources.

Animals↗

PubMed1990

Comparison of relaxation responses of vascular and non-vascular smooth muscle to endothelium-derived relaxing factor (EDRF), acidified sodium nitrite (NO) and sodium nitroprusside.

Smooth muscle relaxant activity of endothelium-derived relaxing factor (EDRF) released from columns of cultured bovine endothelial cells by bradykinin (0.1-3 nmol/l) was measured in four non-vascular preparations: guinea-pig taenia caeci, guinea-pig trachea, rat stomach (fundus) and rat anococcygeus. Each preparation was contracted to a steady level of force with a variety of agonists such that they relaxed optimally to sodium nitroprusside (SNP). The EDRF-induced relaxations in each preparation were compared with those obtained in de-endothelialized ring preparations of greyhound coronary artery by means of paired bioassays run in parallel. EDRF released from the endothelial cell columns caused 80-100% relaxation of the coronary artery, 40-80% in the guinea-pig taenia caeci, 50-70% in the rat anococcygeus, 5-8% in the guinea-pig trachea and was undetectable in the rat stomach strip. By comparison, SNP caused maximal relaxation in all tissues compared with the coronary artery. In separate organ bath experiments the sensitivity to nitric oxide (NO: generated by adding acidified solutions of NaNO2) and SNP was compared in each preparation. SNP caused maximal relaxation in all tissues with the following order of potency: dog coronary artery greater than guinea-pig trachea greater than guinea-pig taenia = rat anococcygeus greater than rat stomach strip. In contrast, the concentration of acidified NaNO2 (NO, 300 nmol/l) that caused 96 +/- 4% relaxation in the dog coronary artery caused 84 +/- 7% and 48 +/- 1% relaxation in the taenia and anococcygeus respectively. No response attributable to NO was detected in either the trachea or rat stomach strip.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1990

The salvage of rabbit ischaemic epigastric free flaps using the vasodilator calcitonin gene-related peptide.

The rabbit epigastric free flap, subjected to 21 hours of warm (25 degrees C) ischaemia, was used as an experimental model to test the ability of two endothelium-dependent vasodilators, calcitonin gene-related peptide (CGRP) and carbamyl beta-methylcholine chloride (MCh, bethanechol chloride, the stable acetylcholine analogue) to improve flap viability. After the period of ischaemia, flaps were infused intra-arterially with either Hanks balanced salt solution (controls), CGRP or MCh for 30 minutes, and received additional intravenous boluses of these drugs at 2 and 32 minutes after revascularisation. The area of flap surviving improved significantly (p less than 0.025) from 39.9% (n = 18) for controls to 70.2% (n = 14) for CGRP treatment at 2 micrograms/kg, but was unchanged at 47.1% (n = 14) for MCh treatment at 50 micrograms/kg. Both CGRP and MCh significantly increased blood flow (p less than 0.05) resulting in 34% lower peripheral resistances compared with controls. These results suggest that CGRP has considerable clinical potential for the salvage of ischaemic flaps. CGRP must have several, as yet undefined, beneficial effects on the ischaemic tissue, since MCh invoked a vasodilatory response but failed to salvage ischaemic flaps.

Abdominal Muscles↗

PubMed1990

Altered venous responses to vasoconstrictor agonists and nerve stimulation in human primary hypertension.

The reactivity of human veins, biopsied from the forearms of 15 patients with untreated primary hypertension and 14 normotensive subjects, was studied in vitro. Veins of hypertensive patients were less distensible since the slope of their wall tension-circumference relationships was steeper than in normotensive subjects. There was no difference between the groups with regard to their sensitivity (location of the concentration corresponding to 50% of the maximum response) or their normalized maximum contractile force (Fmax/unit radius) in response to potassium or serotonin. However, veins from hypertensive subjects were less sensitive to noradrenaline and the selective alpha 2-adrenoceptor agonist UK14304, and showed a fall in normalized Fmax with all alpha-adrenoceptor agonists. In contrast, in veins from hypertensive subjects, normalized Fmax was 3.7 times higher in response to angiotensin II than in veins from normotensive subjects. Despite the reduced responses to exogenous alpha-adrenoceptor agonists, contractile responses to transmural field stimulation were enhanced in veins from hypertensive patients. There was no evidence of medial hypertrophy in the veins of hypertensive subjects. The effect of selective alpha 2-adrenoceptor blockade suggested a decrease in prejunctional autoinhibition, while the effect of desipramine on field stimulation and tritiated noradrenaline efflux suggested a decreased neuronal amine uptake in veins of hypertensive subjects. We conclude that veins in hypertension are stiffer, have reduced alpha-adrenoceptor responsiveness, and generate a greater Fmax in response to angiotensin II and nerve stimulation when compared with veins from normotensive subjects.

Adult↗

PubMed1990

Omega-conotoxin GVIA, the N-type calcium channel inhibitor, is sympatholytic but not vagolytic: consequences for hemodynamics and autonomic reflexes in conscious rabbits.

We investigated the effects of the N-type calcium channel blocking agent, omega-conotoxin GVIA, on the resting hemodynamics and on some autonomic reflexes in the conscious rabbit. omega-Conotoxin 3 and 10 micrograms/kg i.v. reduced mean arterial blood pressure by 16 +/- 2 and 25 +/- 3 mm Hg, respectively, over 30 min accompanied by a tachycardia. Renal vascular conductance (Doppler flowmeter) increased by 27.6 +/- 3.7 and 38.6 +/- 10.3% at 30 min after omega-conotoxin 3 and 10 micrograms/kg, respectively. Vasodilatation was also observed but to a lesser extent in the hindquarter and mesenteric vascular beds. The baroreceptor-heart rate reflex was evoked by a drug method (bolus injection of sodium nitroprusside and phenylephrine) and by inflation of perivascular balloons implanted on the thoracic vena cava and aorta. omega-Conotoxin (3 micrograms/kg) abolished the sympathetic component of the cardiac baroreceptor reflex without affecting vagal efferent activity. In addition, marked vagal-mediated bradycardia from (a) the "Bezold-Jarisch-like" reflex evoked by serotonin (1-10 micrograms/kg i.v.) and (b) the nasopharyngeal reflex evoked by cigarette smoke were unaffected by omega-conotoxin (3-10 micrograms/kg). We conclude that omega-conotoxin-induced N-type calcium channel blockade abolishes sympathetic but not vagal cardiac efferent activity. The hypotension and peripheral vasodilatation are probably due to the prejunctional sympatholytic action of the peptide. These N-type calcium channels are thus limited to the sympathetic varicosities in the rabbit.

Analysis of Variance↗

PubMed1990

Contractile responses to alpha 1-adrenoceptor stimulation during maturation in the aorta of the normotensive and spontaneously hypertensive rat: relation to structure.

1. The significantly greater rise in blood pressure during the first 20 weeks of life in spontaneously hypertensive rats (SHR) when compared with normotensive Wistar-Kyoto rats (WKY) may be related to increased vasoconstrictor responses caused by enhanced transmitter release or post-junctional receptor changes. 2. The reactivity of rat isolated aorta to post-junctional alpha 1-adrenoceptor stimulation by methoxamine and to transmural sympathetic nerve stimulation was studied in ring segments suspended at equivalent transmural pressures in organ baths. 3. Wall stress in the SHR aorta was significantly higher at 4 weeks, but lower at 9 and 20 weeks when compared with the WKY aorta, a possible adaptation to the higher pressures seen in the SHR at the latter ages. 4. The sensitivity (location of EC50) to methoxamine was similar at all ages in both strains, but the SHR aortae at 9 and 20 weeks generated higher maximal contractile force to this agent compared with the WKY aorta. 5. The increase in force to methoxamine parallelled the medial hypertrophy of the SHR aorta, determined from computerized morphometric analysis. 6. There was an enhanced response to transmural field stimulation in the SHR aortae at 9 weeks, that was not accounted for by medial hypertrophy or altered neuronal uptake of noradrenaline. 7. These studies suggest that enhanced maximal contractile force in the SHR aorta to alpha 1-adrenoceptor stimulation is accounted for by medial hypertrophy. However, there is an additional enhanced reactivity at 9 weeks in response to nerve stimulation in the SHR aorta that may be related to increased innervation density.

Adrenergic alpha-Agonists↗

PubMed1990

Omega-conotoxin GVIA is a potent inhibitor of sympathetic neurogenic responses in rat small mesenteric arteries.

1. We have investigated the effects of the N-type calcium channel blocker, omega-conotoxin GVIA, on contractile responses to nerve stimulation, noradrenaline and KCl in rat small mesenteric arteries. In separate experiments, single and summated excitatory junctional potentials (e.j.ps) evoked by nerve stimulation were recorded with an intracellular electrode in the absence and presence of omega-conotoxin. 2. Electrical field stimulation of intramural sympathetic nerves (30 V; 0.25 ms pulse width; 3 s train length; 4-24 Hz) caused frequency-dependent contractions. Cumulative concentration-response curves for the contractions induced by noradrenaline and KCl were constructed in the same preparations. Stimulation at 0.2 Hz and 10 Hz induced respectively single e.j.ps without contractions and summated e.j.ps associated with a contractile response. 3. omega-Conotoxin (0.1 to 3 nM) inhibited markedly and in a concentration-dependent manner both the contractions and e.j.ps to electrical field stimulation. The concentration-response curves to exogenous noradrenaline and KCl remained unaffected. 4. The time-course for the effects of omega-conotoxin (0.3 to 3 nM) indicated a slow onset of action with at least one hour to achieve an equilibrium. 5. The experiments indicate that omega-conotoxin acts prejunctionally to inhibit sympathetic neurotransmission in rat small arteries presumably by inhibition of noradrenaline release. We suggest that omega-conotoxin could be a useful tool to study the control of vascular tone through the autonomic nervous system.

Animals↗

PubMed1990

Characterization of responses to cromakalim and pinacidil in smooth and cardiac muscle by use of selective antagonists.

1. In dog isolated coronary artery (precontracted with endothelin, 10 nM) cromakalim (0.1-30 microM) and pinacidil (1-30 microM) produced concentration-dependent vasorelaxant responses. The effects of these compounds could be blocked by glibenclamide (3 microM), phentolamine (30 microM) or alinidine (30 microM) to a similar extent, indicating that both agents alter vascular tone through the same mechanism in this preparation. 2. The ability of the antagonists glibenclamide, phentolamine and alinidine to block the response to cromakalim in a number of smooth muscle types from the guniea-pig was determined. Cromakalim (0.1-30 microM) produced concentration-dependent relaxant responses in thoracic aorta (precontracted with endothelin, 30 nM), ileum (precontracted with K+, 25 mM) and trachea (spontaneously contracted). Responses to cromakalim in all tissues could be blocked by the three antagonists. However, significantly higher concentrations of the antagonists were required to block responses in the thoracic aorta than in the ileum or trachea. Given that the rank order of potency of the antagonists was similar in all tissues (i.e. glibenclamide greater than phentolamine = alinidine), this result may suggest vascular K+ channels opened by cromakalim are quantitatively but not qualitatively different in vascular compared with non-vascular smooth muscle. Glibenclamide was approximately 10 times more potent than phentolamine or alinidine. 3. Cromakalim had minimal functional effects on the rat spontaneously beating right atrial (rate) or electrically driven left ventricular strip (force) preparations. Similarly the three antagonists studied failed to alter force generation in the right ventricular strip. However alinidine and phentolamine did produce a dose-related bradycardia in the spontaneously beating right atria. This effect appears to be unrelated to blockade of the K+ channel opened by cromakalim since glibenclamide, the most potent K+ channel antagonist studied, failed to produce the same response. 4. It would appear that the K+ channel opened by cromakalim is present in a number of vascular and non-vascular smooth muscle. Based on the potency of the three antagonists studied, there appears to be little heterogeneity in the process activated by cromakalim in vascular and non-vascular smooth muscle.

Animals↗