Biomedical subjects

J F Giudicelli

Publications and source records attributed to J F Giudicelli.

At least 19 recordsLinked to original sources

PubMed1995

Endothelial modulation of beta-adrenergic dilation of large coronary arteries in conscious dogs.

BACKGROUND: Endothelium-derived relaxing factors have been described as important intermediates in beta-adrenergic vasodilation of resistance coronary vessels, but their involvement at the level of large epicardial coronary arteries remains controversial. Therefore, we examined the role of vascular endothelium in the beta-adrenergic-mediated vasodilation of large epicardial coronary arteries in conscious dogs. METHODS AND RESULTS: Nine dogs were instrumented for measurement of left circumflex coronary artery diameter (CD) by sonomicrometry and coronary blood flow velocity (CBFv) with a Doppler technique in response to graded doses of isoproterenol (0.001 to 0.1 microgram/kg IV bolus). Under control conditions, isoproterenol induced dose-dependent increases in CD and CBFv. When CBFv was kept constant at its baseline value by inflation of a cuff occluder, isoproterenol still induced dose-dependent increases in CD, but the latter were of lesser magnitude than those observed under normal CBFv conditions (110 +/- 20 versus 170 +/- 30 microns, respectively, ie, a reduction of 33% of the dilatory response at 0.1 microgram/kg, P < .01). In the same dogs, the coronary endothelium was then mechanically removed at the site of CD measurement by a balloon angioplasty technique. After this procedure, the dose-dependent increases in CD induced by isoproterenol under either normal or controlled CBFv conditions were overimposable, and their magnitude was similar to that of the increases observed in the presence of an intact endothelium when CBFv was kept constant. After beta 1-adrenergic receptor blockade by atenolol (1 mg/kg), isoproterenol-induced increases in CD were abolished either when CBFv was kept constant or after endothelium removal. CONCLUSIONS: In conscious dogs, the direct stimulating effect of isoproterenol on beta 1-adrenergic receptors is endothelium-independent at the level of large coronary arteries. The endothelium reinforces the dilatory response to isoproterenol through an indirect, flow-dependent mechanism.

Adrenergic beta-Agonists↗

PubMed1995

Early and late haemodynamic and morphological effects of angiotensin II subtype 1 receptor blockade during genetic hypertension development.

OBJECTIVE: To investigate the haemodynamic and morphological effects resulting from the chronic administration to young spontaneously hypertensive rats (SHR) of a new selective angiotensin II subtype 1 (AT1) receptor antagonist, SR 47436/BMS-186295 (SR/BMS) both during and after the treatment period. METHODS: SR/BMS (60 mg/kg per day, orally) or distilled water was chronically (from 4 to 20 weeks of age) administered to SHR. At age 8, 14, 20 and 28 weeks the effects of SR/BMS on the systemic and regional haemodynamic (radioactive microsphere technique) and the cardiac and vascular morphological parameters (automatic image analysis) were investigated. RESULTS: SR/BMS limited genetic hypertension development and opposed the age-related rises in total peripheral and regional vascular resistances. Simultaneously, it limited the age-related increases in heart weight, left ventricular cross-sectional area and collagen content. Age-related increases in aortic media thickness and amount of collagen were also significantly reduced, whereas aortic compliance was increased. Eight weeks after withdrawal of treatment the antihypertensive effect of SR/BMS, although attenuated, and the limitation of cardiac and vascular remodelling, persisted. CONCLUSIONS: Early AT1 receptor blockade in SHR opposes genetic hypertension development during the treatment period and persistently after its interruption. Prevention of genetic hypertension development during the treatment period can be accounted for by the limitation of the age-related development of the haemodynamic and morphological abnormalities, whereas the persistence of the antihypertensive effect observed after drug withdrawal is due mainly to a maintained prevention of the development of the cardiovascular morphological alterations.

Angiotensin Receptor Antagonists↗

PubMed1995

Comparisons of the effects of nicorandil, pinacidil, nicardipine and nitroglycerin on coronary vessels in the conscious dog: role of the endothelium.

1. The vasodilator properties of nicorandil on large and small coronary arteries were compared to those of nicardipine, pinacidil, nitroglycerin and acetylcholine in six conscious dogs. 2. Intravenous bolus injections of acetylcholine (0.1 micrograms kg-1), nitroglycerin (0.3-3 micrograms kg-1), pinacidil (10-100 micrograms kg-1), nicardipine (3-30 micrograms kg-1) and nicorandil (10-100 micrograms kg-1) dose-dependently increased circumflex coronary artery diameter and decreased coronary vascular resistance, indicating vasodilator effects on both conduit and resistance coronary arteries. 3. Three days after removal of the endothelium of the circumflex coronary artery (balloon angioplasty), pinacidil- and nicardipine-induced dilation of large coronary arteries was greatly reduced (both -76%, P < 0.01) whereas that produced by nitroglycerin and nicorandil was decreased only slightly and to a similar extent for both drugs (-19%, P < 0.01 and -28%, P < 0.05, respectively). 4. Thus in conscious dogs, nicardipine- and pinacidil-induced dilatation of large coronary arteries is endothelium-dependent. In contrast, the vasodilator effects of nitroglycerin and nicorandil on conduit vessels are endothelium-independent. 5. Finally, our results demonstrate that nicorandil dilates the large coronary arteries through its nitrate-like action and that the ATP-potassium channel opening properties of the drug are not involved in this effect in the conscious dog.

Acetylcholine↗

PubMed1995

Coronary and hemodynamic effects of S 16257, a new bradycardic agent, in resting and exercising conscious dogs.

The effects of (7,8-dimethoxy 3-[3-([(1S)-(4,5-dimethoxybenzocyclobutan-1-yl)methyl]methylamino) - propyl]1,3,4,5-tetrahydro-2H-benzapin 2-one hydrochloride) (S 16257), a new bradycardic agent acting through inhibition of the hyperpolarization-activated I(f) current in the sino-atrial node, on arterial blood pressure, cardiac output, left ventricular pressure and dP/dt, epicardial coronary artery diameter and coronary blood flow velocity were investigated at graded doses (0.1 to 1 mg/kg) and compared to those of propranolol (1 mg/kg) and saline in chronically instrumented conscious dogs. At rest, S 16257 induced a dose-dependent bradycardia that was significant at 0.5 (-16% +/- 3%) and 1 mg/kg (-23% +/- 3%). At 0.5 mg/kg, S 16257 decreased both resting HR and treadmill exercise-induced tachycardia to a similar extent as propranolol. However, in contrast to propranolol, S 16257 (0.5 mg/kg) did not affect the increase in mean coronary blood flow velocity and the decrease in coronary vascular resistance observed during a control exercise performed under saline. In addition, S 16257 did not affect resting epicardial coronary artery diameter and only attenuated its increase during exercise, whereas propranolol reduced it at rest and maintained a significant constriction of these large vessels throughout the exercise period. Propranolol, but not S 16257, decreased left ventricular dP/dt at each stage of exercise.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1994

Effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction.

This study investigated the effects of two K+ channel openers, aprikalim and pinacidil, on hypoxic pulmonary vasoconstriction induced in isolated rat lung perfused at constant flow. In order to evaluate the mechanism of the hypoxic vasoconstriction we also studied the effects of an inhibitor of the endothelium-derived relaxing factor (EDRF), NG-nitro-L-arginine methyl ester (100 microM), an inhibitor of the guanylate cyclase, methylene blue (30 microM), two K+ channel blockers, glibenclamide (1 microM) and tetraethylammonium (20 mM). In normoxia, NG-nitro-L-arginine methyl ester, methylene blue, glibenclamide or tetraethylammonium did not enhance significantly the baseline perfusion pressure, suggesting that neither EDRF nor K+ channels are involved in the modulation of the low basal pulmonary vascular tone. In hypoxia, aprikalim and pinacidil (0.03-3 microM) induced a concentration-dependent decrease of pulmonary pressure, exhibiting their spasmolytic effects in acute hypoxia. The hypoxic pressure response was significantly increased by NG-nitro-L-arginine methyl ester, methylene blue and tetraethylammonium, but not by glibenclamide suggesting that EDRF and K+ channels other than ATP-sensitive K+ channels are involved in the modulation of the hypoxic pressure response. The spasmolytic effects of aprikalim and pinacidil (1 microM) were not modified by NG-nitro-L-arginine methyl ester, but were partially reduced by tetraethylammonium and completely abolished by glibenclamide, suggesting that these effects are mainly but not exclusively mediated through ATP-sensitive K+ channel opening.

Animals↗

PubMed1994

Comparison of the effects of dilevalol and propranolol on systemic and regional haemodynamics in healthy volunteers at rest and during exercise.

The effects of single oral doses of dilevalol 400 mg and propranolol 80 mg on systemic and regional haemodynamics at rest and after sub-maximal exercise, were compared, in a placebo-controlled, randomised, double-blind, crossover study in 6 healthy male volunteers. At rest, as compared to placebo, neither dilevalol nor propranolol significantly affected arterial pressure and heart rate but, whereas propranolol decreased cardiac output (-27% at 2 h) and tended to increase total peripheral resistance, dilevalol tended to increase cardiac output and decreased total peripheral resistance (-7% at 2 h). Neither dilevalol nor propranolol affected brachial artery diameter. Propranolol tended to decrease brachial artery flow (-20% at 2 h) and to increase brachial vascular resistance (+25% at 2 h), but dilevalol did not and the brachial irrigation ratios did not change. Neither of the drugs affected carotid haemodynamics or plasma atrial natriuretic factor. Both drugs tended to decrease plasma renin activity, and dilevalol (+82% at 2 h) increased norepinephrine more than propranolol (+19% at 2 h). After exercise, dilevalol and propranolol produced similar falls in the induced increases in arterial pressure, heart rate and cardiac output, and had the same effects on regional haemodynamics, plasma renin activity and atrial natriuretic factor. Finally, dilevalol greatly increased plasma norepinephrine. We conclude that the beta 2-adrenoceptor agonist activity of dilevalol was clearly expressed at rest, thus inducing vasodilation and counteracting the beta-adrenoceptor blockade-induced negative chronotropic and inotropic effects. However, during sub-maximal exercise, only the beta-adrenoceptor antagonist activity of dilevalol was apparent.

Adult↗

PubMed1994

Influence of chronic angiotensin-converting enzyme inhibition on anesthetic induction.

BACKGROUND: Several cases of hypotension have been reported in patients who received angiotensin-converting enzyme inhibitors (ACEIs) before a surgical procedure, suggesting that interactions between ACEIs and anesthesia may be neither beneficial nor predictable. To determine if continuation of ACEI therapy until the morning of surgery leads to an unacceptable decrease in blood pressure on induction, we investigated 51 vascular surgical patients that were chronically treated for hypertension with either captopril or enalapril. METHODS: After randomization, ACEI therapy was either continued until the morning of surgery or stopped at the time of the preanesthetic visit, at least 12 h (captopril) or 24 h (enalapril) before surgery. Each patient received a standardized anesthetic induction. If systolic blood pressure (monitored using a radial artery cannula) decreased to less than 90 mmHg in response to induction, ephedrine was administered. RESULTS: A marked decrease in plasma converting-enzyme activity was found in patients who received enalapril until the morning of the surgical procedure, and 100% of them required ephedrine after induction. In patients who received their usual dose of captopril on the morning of surgery, plasma converting-enzyme activity was reduced to a lesser extent (when compared with patients who received enalapril). Finally, in the patients in whom ACEI therapy, either enalapril or captopril, was stopped of the evening before surgery, the incidence of induction-induced hypotension was significantly less when enalapril or captopril therapy has been discontinued. CONCLUSIONS: These data indicate that in hypertensive patients chronically treated with ACEIs, maintenance of therapy until the day of surgery may increase the probability of hypotension at induction.

Anesthesia↗

PubMed1994

Noninvasive assessment of regional arteriolar and arterial dilating properties of lisinopril in healthy volunteers.

The effects of single oral doses of lisinopril (5 and 20 mg) on systemic and regional hemodynamics were investigated noninvasively in a placebo-controlled, randomized, double-blind, cross-over study of 6 healthy male volunteers. Lisinopril induced a dose-dependent (significant after 20 mg) and long-lasting (< or = 8 h) decrease in mean arterial pressure (MAP, approximately 11% after 20 mg) that was related to a decrease in total peripheral resistance (TPR), because simultaneously heart rate (HR) and cardiac output (CO) were unchanged. Brachial artery flow (+42 and +47% after 5 and 20 mg, respectively) and diameter (+8 and +9%) increased significantly, whereas brachial vascular resistance (-31 and -38%) decreased significantly from 2 to 8 h after drug intake. Common carotid artery flow (+20 and +24%) also increased significantly, whereas corresponding resistance (-18 and -26%) decreased significantly during the same period. Finally, CO was significantly redistributed toward the brachial and, to a lesser extent, the carotid vascular beds after both doses of lisinopril. We conclude that in healthy subjects lisinopril, at non- or slightly hypotensive doses, dilates both arterioles and large arteries and that this vasodilation is not homogeneous, affecting preferentially the brachial rather than the carotid vascular bed.

Administration, Oral↗

PubMed1994

Pharmacokinetic-pharmacodynamic modeling between pinacidil or pinacidil-N-oxide plasma levels and systemic and regional hemodynamic effects in healthy volunteers.

Pinacidil (P) lowers blood pressure through peripheral vasodilation, but also induces dose-dependent side-effects. In a previous placebo-controlled, randomized, double-blind and crossover study, performed in six healthy male volunteers, we investigated the systemic and regional hemodynamic effects of a single oral administration of 25 mg of P (sustained-release form) and measured the plasma concentrations of P and of its active metabolite, pinacidil-N-oxide (PO). In the present study, our goal has been to investigate the relationships between P and/or PO plasma concentrations and P administration effects on systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), brachial and carotid arteries' diameters (BAD, CAD), flows (BAF, CAF) and vascular resistances (BVR, CVR) which were assessed before and at different time intervals after drug intake. Concentration-effect relationships were investigated using both linear and log-linear multiple regression models with P, PO or both P and PO as independent variables (six models). Significant linear relationships were observed between P and/or PO and SAP, DAP, MAP, TPR, BAD, BAF, BVR, CAD and CVR. For example, TPR (dynes.s/cm5) = 1308-3.031 x P (ng/ml), R = 0.57, P = 0.0037; BVR (mmHg.s/ml) = 58-0.261 x P (ng/ml), R = 0.56, P = 0.0042. Almost similar R values were obtained using P, PO, or both P and PO. The use of log-linear models did not improve the fittings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1994

Lack of importance of NO in beta-adrenoceptor-mediated relaxation of large epicardial canine coronary arteries.

This study was designed to test the role of endothelium and the L-arginine/NO pathway in the relaxation of canine large coronary arteries to the beta-adrenoceptor agonist, isoprenaline. Relaxation of left circumflex (LCX) and left anterior descending (LAD) coronary arteries were measured in organ baths after contraction with the thromboxane analogue, U46619, either in absence or in presence of endothelium and in LCX arteries after pretreatment with NG-nitro-L-arginine-methyl-ester (L-NAME). LAD arteries with and without endothelium relaxed identically to isoprenaline but their maximal relaxation was smaller than corresponding LCX arteries with endothelium. A slight but non significant difference was observed in LCX arteries with endothelium as compared to rings without endothelium or pretreated with L-NAME. No difference was observed in the relaxation of LCX arteries to forskolin in arteries with or without endothelium. These results suggest that endothelium is not essential and that NO is not directly involved in the relaxation of large coronary arteries induced by isoprenaline.

Animals↗

PubMed1994

Hydralazine dilates large epicardial coronary arteries in conscious dogs through an endothelium-independent mechanism.

In chronically instrumented conscious dogs, hydralazine (30-300 micrograms/kg) and nitroglycerin (NTG 0.03-10 micrograms/kg) dose-dependently dilated large epicardial coronary arteries. Simultaneously, hydralazine also dose-dependently dilated small coronary arteries, whereas a similar effect was observed only after NTG > 0.3 microgram/kg. When large coronary arteries were deendothelialized by a balloon angioplasty catheter, dilation of large coronary arteries in response to acetylcholine (ACh 0.3 microgram/kg) and to reactive hyperemia was reduced by 87 and 95%, respectively. In contrast, vasodilation of large coronary arteries induced by hydralazine and NTG was only minimally and similarly affected (-19% for both drugs). These findings demonstrate that in vivo hydralazine-induced dilation of large coronary arteries is endothelium independent.

Angioplasty, Balloon↗

PubMed1993

Differential effects of celiprolol and atenolol on large epicardial coronary arteries in conscious dogs at rest and during exercise.

The effects of celiprolol (1 mg/kg), a selective beta 1-adrenoceptor antagonist with partial agonist activity (PAA), on large and small coronary arteries and on systemic hemodynamics were investigated and compared with those of atenolol (1 mg/kg) and saline at rest and during three levels of treadmill exercise in the same 7 conscious dogs. Control exercise after saline administration induced increases in heart rate (HR 131 +/- 4%), left ventricular (LVdP/dt 117 +/- 5%), coronary blood flow (CBF 133 +/- 13%), and circumflex artery diameter (CxAD, 6.6 +/- 1.3%) and a decrease in coronary vascular resistance (CVR, -47 +/- 3%). Atenolol decreased LVdP/dt (-19 +/- 2%) and CxAD (-3.2 +/- 0.3%, p < 0.05) at rest, but large epicardial coronary arteries remained constricted during exercise (-4.7 +/- 1.4% at 12 km/h, p < 0.05) despite simultaneous dilation of coronary resistance vessels. In contrast to atenolol, celiprolol did not constrict large coronary arteries at rest (CxAD -0.2 +/- 0.9%, NS), and this beneficial effect of celiprolol was maintained throughout the exercise period. LVdP/dt was not modified and HR was slightly increased (14.3 +/- 2.6%) at rest by celiprolol. Atenolol and celiprolol reduced the exercise-induced positive inotropic and chronotropic effects, atenolol being the most potent. Thus, in dogs at rest when basal sympathetic tone was low, celiprolol, most likely because of its PAA, induced slight cardiac stimulation and prevented vasoconstriction of the large coronary arteries usually observed after beta-adrenoceptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Systemic and coronary effects of the angiotensin II receptor antagonist EXP3174 in dogs.

The effects of EXP3174 (0.03-0.3 mg/kg), the active metabolite of the angiotensin II (AII) receptor antagonist losartan, on systemic and coronary hemodynamics as well as on regional myocardial blood flow (radioactive microspheres) were evaluated in anesthetized, open-chest dogs with or without preactivated renin-angiotensin system (RAS) (furosemide treatment). These effects were compared with those of the angiotensin-converting enzyme (ACE) inhibitor enalaprilat (0.1-1 mg/kg). In dogs without preactivated RAS, EXP3174 or enalaprilat did not exert marked hemodynamic effects other did not exert marked hemodynamic effects other than a significant decrease in mean arterial blood pressure (MAP) at the highest doses. In dogs with preactivated RAS, EXP3174 induced a marked, dose-dependent decrease in MAP (maximum decrease -23 +/- 7%), associated with a significant decrease in total peripheral resistance (TPR), whereas cardiac output (CO), heart rate (HR), and left ventricular dP/dt remained unchanged. At the coronary level, EXP3174 induced a decrease in mean coronary resistance that paralleled that of AP. Similar systemic and coronary hemodynamic effects were obtained with enalaprilat administered at doses three times higher. However, regional myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural) or its transmural distribution (endo/epi ratios) was not affected by EXP3174 or enalaprilat. Thus, these results indicate that blockade of the AT1 receptor of AII by EXP3174 induces hemodynamic modifications similar to those evoked by the ACE inhibitor enalaprilat. The lack of effect of EXP3174 or enalaprilat on regional myocardial blood flow (RMBF) suggests, however, that the RAS does not play a role in regulation of myocardial tissue perfusion.

Angiotensin I↗

PubMed1993

Sympathoinhibitory effects of losartan in spontaneously hypertensive rats.

Nonselective inhibition of endogenous angiotensin II (AII) by AI-converting enzyme inhibitors (ACEI) results in sympathoinhibitory effects. We wished to examine the influence of selective inhibition of endogenous AII by losartan, a nonpeptide AT1-receptor antagonist, on the sympathetic system. Cardiac, systemic, and regional vascular (kidney, mesentery, hindlimb) responses to selective alpha 1- and alpha 2-adrenoceptor agonists and to electrical stimulation of the spinal cord were investigated in pithed spontaneously hypertensive rats (SHR) by pulsed Doppler technique. Losartan (10 mg/kg) was administered orally, either as a single dose or for 8 successive days. Under both conditions, AII systemic pressor, regional vasoconstrictor, and tachycardic responses were completely abolished by losartan. At the vascular level, losartan did not affect postsynaptic alpha 1-adrenoceptor-mediated systemic pressor and regional vasconstrictor responses, but reduced postsynaptic alpha 2-adrenoceptor-mediated renal vasoconstriction. Losartan significantly decreased the systemic pressor and regional vasoconstrictor responses elicited by spinal cord stimulation. This sympathoinhibitory effect was not homogeneously distributed, preferentially affecting the kidney. At the cardiac level, spinal cord stimulation induced a strong tachycardia which remained unaffected by losartan. Thus in SHR, losartan exerts sympathoinhibitory effects against the vascular but not the cardiac responses to spinal cord stimulation. Because the vascular responses to postjunctional alpha 1- and alpha 2-adrenoceptor stimulation, except in the kidney, simultaneously remain poorly affected, the sympathoinhibitory effects of losartan mainly develop prejunctionally through AT1-receptors blockade.

Adrenergic alpha-Agonists↗

PubMed1993

Losartan's protective effects in stroke-prone spontaneously hypertensive rats persist durably after treatment withdrawal.

The effects of long-term oral administration of losartan on the occurrence of stroke and on mortality were investigated in young salt-loaded stroke-prone spontaneously hypertensive rats (SHR-SPs) during the treatment period (5-20 weeks of age) and up to 8 weeks thereafter. Two doses of losartan, 1 and 10 mg/kg/day, were investigated, which afforded no and only moderate antihypertensive effects, respectively. During the treatment period, losartan at both doses completely suppressed stroke and mortality and strongly opposed (low dose) or abolished (high dose) the increases in saline intake, diuresis, and proteinuria observed in controls. It markedly limited (low dose) or abolished (high dose) vascular fibrinoid necrosis formation in the brain, kidneys, and heart. Finally, losartan, especially at the high dose, reduced arterial thickening and glomerular and tubulo-interstitial lesions in the kidneys, as well as arterial thickening, infarction, and fibrosis in the heart. Eight weeks after treatment discontinuation, all animals but one (low dose) were still alive. Vascular fibrinoid necrosis development remained strongly prevented (low dose) or fully suppressed (high dose) in all investigated organs. Finally, cardiac and renal lesions tended to worsen, and proteinuria was noted only in the low-dose group. We conclude that in SHR-SPs, angiotensin II, through AT1 receptor stimulation, most likely plays a major role in fibrinoid necrosis formation, vascular proliferative changes, and stroke occurrence and that losartan, most likely independently of its effect on blood pressure, affords a full and long-lasting protection against stroke and mortality both during and after the treatment period.

Aging↗

PubMed1993

Effects of an angiotensin-converting enzyme inhibitor, lisinopril, on cerebral blood flow autoregulation in healthy volunteers.

The effects of a single oral dose (20 mg) of lisinopril on systemic, carotid (pulsed Doppler), and cerebral (middle cerebral artery, transcranial Doppler) hemodynamics have been investigated over an 8-h period in eight healthy volunteers in a double-blind placebo-controlled crossover study. In addition, cerebral vasodilatory reserve was measured (acetazolamide test). Lisinopril did not affect systemic hemodynamics but it increased both common carotid artery blood flow (+26.2%, p < 0.01) and diameter (+4.5%, p < 0.05) after 8 h. Lisinopril did not affect middle cerebral artery mean blood flow velocity but increased cerebral resistance index (+8.1%, p < 0.05) at 4 h and cerebral vasodilatory reserve (+24.8%, p < 0.05). These data suggest that lisinopril produces a paradoxical vasoconstriction of the small cerebral arterioles. This vasoconstriction might be a compensatory mechanism to a dilation of large cerebral arteries, thus resulting in an unchanged cerebral blood flow.

Acetazolamide↗

PubMed1993

Alpha 1 and alpha 2-adrenergic control of large and small coronary arteries during exercise in conscious dogs under beta-blockade.

The aim of this study was to determine the relative roles of alpha 1-and alpha 2-adrenoceptors at the level of large epicardial and small resistance coronary arteries when sympathetic tone is increased by exercise in conscious dogs. The responses of left circumflex coronary artery diameter and blood flow were investigated at rest and during graded treadmill exercise (5, 10 and 12 km/h) in six chronically instrumented dogs during control conditions (saline) and after administration of propranolol (1 mg/kg) either alone or in combination with either prazosin (50 micrograms/kg), or idazoxan (300 micrograms/kg), or the association of prazosin+idazoxan (same doses). In control conditions, graded treadmill exercise resulted in a progressive increase in coronary artery diameter (+3.8 +/- 0.6% from 3479 +/- 80 microns) and in a decrease in coronary vascular resistance (-46.0 +/- 4.5% from 8.49 +/- 1.51 mmHg/cm/s). Propranolol significantly constricted large (-4.4 +/- 0.6% from 3486 +/- 87 microns) and limited dilation of small coronary arteries during exercise. These coronary effects of propranolol remained unchanged following additional alpha 2-adrenoceptor blockade by idazoxan but were abolished following alpha 1-adrenoceptor blockade by prazosin, given either alone or combined with idazoxan. Thus, alpha 1- but not alpha 2-adrenoceptors are responsible for propranolol-induced constriction of large coronary arteries and limitation of small coronary arteries dilation during exercise in conscious dogs.

Adrenergic beta-Antagonists↗

PubMed1993

The role of NO release in the control of large and small coronary artery tone in conscious dogs.

Intravenous administration of the nitric oxide donor CAS 754 (10-100 micrograms/kg) elicited a long-lasting, highly selective, and dose-dependent increase in large epicardial coronary diameter in conscious dogs, whereas nitroglycerin (up to 0.3 micrograms/kg) induced a shorter and less selective dilation of the large conductance vessels. In contrast, acetylcholine simultaneously increased large epicardial coronary artery diameter and decreased coronary resistance, regardless of the doses administered (0.01-3 micrograms/kg). Three days after endothelium removal by limited coronary angioplasty, the vasodilator effects of acetylcholine and reactive hyperemia were suppressed, whereas those induced by CAS 754 and nitroglycerin were not significantly different from those observed before endothelium removal. These data show that the epicardial coronary vasodilator effects of both CAS 754 and nitroglycerin are endothelium-independent in vivo. Thus, the unique pharmacological profile of CAS 754 on coronary dynamics could prove to be of major importance in the treatment of angina pectoris.

Acetylcholine↗