Biomedical subjects

D J Duncker

Publications and source records attributed to D J Duncker.

At least 109 records · Page 6Linked to original sources

PubMed1990

Haemodynamic profile of the potassium channel activator EMD 52692 in anaesthetized pigs.

1. The systemic and regional haemodynamic effects of the potassium channel activator EMD 52692 or its solvent were investigated after intravenous and after intracoronary administration in anaesthetized pigs. 2. Consecutive intravenous 10 min infusions of EMD 52692 (0.15, 0.30, 0.60, 1.20 micrograms kg-1 min-1; n = 7) dose-dependently decreased mean arterial blood pressure by up to 50%. This was entirely due to peripheral vasodilatation, since cardiac output did not change. Heart rate increased by up to 50%, while left ventricular end diastolic pressure decreased dose-dependently from 6 +/- 1 mmHg to 3 +/- 1 mmHg (P less than 0.05), and stroke volume decreased from 30 +/- 2 ml to 21 +/- 2 ml (P less than 0.05). Left ventricular dP/dtmax was not affected. 3. Although cardiac output did not change, EMD 52692 caused a redistribution of blood flow from the arteriovenous anastomoses to the capillary channels. Blood flow to the adrenals, small intestine, stomach, bladder, spleen and brain increased, while renal blood flow decreased and blood flow to several muscle groups and skin were not altered. Vascular conductance was increased dose-dependently in all organs, except for the kidneys, where after the initial increase, vascular conductance returned to baseline with the highest dose. Particularly striking were the effects on the vasculature of the brain. With the highest dose of EMD 52692 blood flow more than doubled, while vascular conductance increased four fold. 4. Transmural myocardial blood flow increased slightly, which was entirely due to an increase in subepicardial blood flow. Myocardial O2-consumption and segment length shortening were not significantly affected. 5. After consecutive 10 min intracoronary infusions (0.0095, 0.019, 0.0375 and 0.075 microgram kg-1 min-1; n = 7) into the left anterior descending coronary artery (LADCA), mean arterial blood pressure was maintained with the lowest two doses, but decreased by up to 15% with the higher doses, whereas heart rate increased by up to 24%. Blood flow to the LADCA-perfused myocardium doubled with the highest dose, the subepicardium benefitting the most. Coronary venous O2-saturation increased dose-dependently from 23 +/- 2% to 60 +/- 4%, while myocardial O2-consumption of the LADCA-perfused myocardium was not affected by the drug. 6. It is concluded that EMD 52692 is a potent vasodilator, with particularly pronounced effects on vasculature of the brain. Its selectivity for vascular smooth muscle cells exceeds that for the myocytes, since with doses that are much higher than those of potential clinical interest no negative inotropic effects were observed. The compound primarily dilates arteries but some venodilatation may also occur.

Animals↗

PubMed1990

Nimodipine has no effect on the cerebral circulation in conscious pigs, despite an increase in cardiac output.

1. We studied the effects of four doses of nimodipine (0.5, 1, 2 and 4 micrograms kg-1 min-1) on systemic haemodynamics and on regional vascular beds, in particular the cerebral circulation, in conscious pigs. 2. Nimodipine caused dose-dependent, probably reflex-mediated, increases in heart rate (42% with the highest dose) and cardiac output (54%), while arterial blood pressure was only minimally affected. Left ventricular end-diastolic pressure and systemic vascular resistance decreased dose-dependently (35-40% at the highest dose) while stroke volume remained unchanged. 3. Total brain blood flow was not affected by the drug. Furthermore, we could not demonstrate any regional cerebral differences, as blood flows to both cerebral hemispheres as well as the diencephalon, cerebellum and brain stem remained unchanged. 4. Blood flow to the kidneys, liver, small intestine and skin also did not change. Nimodipine caused dose-dependent increases in blood flow to the stomach (95%), myocardium (97%) and adrenal glands (102%), while blood flow to skeletal muscles (267%) increased most. 5. It is concluded that in the conscious pig, nimodipine is an arterial vasodilator which shows some selectivity for the skeletal muscle vasculature but does not increase total or regional cerebral blood flow.

Animals↗

PubMed1989

Acute hemodynamic effects of nisoldipine and pimobendan in conscious pigs with chronic heart failure.

The acute systemic hemodynamic effects of the calcium antagonist nisoldipine and the pyridazinone-derivative pimobendan, a phosphodiesterase inhibitor with vasodilating as well as positive inotropic properties, were studied in conscious pigs with chronic heart failure. Left ventricular (LV) dysfunction, manifested by a 25% decrease in cardiac output (CO), a 35% increase in systemic vascular resistance (SVR), and a doubling of the left ventricular filling pressure, was induced by a proximal ligation of the left circumflex coronary artery. Two to three weeks after myocardial infarction, cumulative 10-min infusions of either nisoldipine (0.05, 0.1, 0.25, and 0.5 micrograms/kg/min), pimobendan (2.5, 5, 12.5, and 25 micrograms/kg/min) or the solvents were administered. Infusion of the solvents did not affect any of the hemodynamic variables. Both nisoldipine and pimobendan normalized CO and exhibited a similar cardiac profile [systemic vasodilatation, reduction in left ventricular filling pressure, and an increase in heart rate (HR)] except for the significantly (p less than 0.05) larger increase in LVdP/dtmax with pimobendan (85%) than with nisoldipine (45%). In animals with heart failure, lower doses of both nisoldipine (twice) and pimobendan (four times) were needed to elicit a 30% reduction in SVR than in animals with normal pump function. For both drugs, the slope of the line describing the vasodilatory and positive inotropic properties shifted more in favor of the vasodilatory actions during heart failure (p less than 0.05). We conclude that in swine with chronic LV dysfunction nisoldipine, despite its lack of inotropic properties, appeared to improve ventricular function to the same extent as the primary positive inotropic agent pimobendan.

Acid-Base Equilibrium↗

PubMed1988

Systemic haemodynamics of dihydropyridine derivatives in conscious pigs with or without propranolol.

The systemic haemodynamic effects of a 10 min i.v. infusion of three dihydropyridine Ca2+ channel blockers, nifedipine (1, 2 and 4 micrograms.kg-1.min-1), nisoldipine (0.5, 1 and 2 micrograms.kg-1.min-1) and nimodipine (1, 2 and 4 micrograms.kg-1.min-1) were studied in instrumented conscious pigs with or without a propranolol-induced beta-adrenoceptor blockade (0.5 mg.kg-1 bolus followed by 0.5 mg.kg-1.h-1). Initial experiments showed that the solvent used for the Ca2+ channel blockers had no haemodynamic effects and that the effects of propranolol wer constant during a 30 min period. Nisoldipine, nimodipine and nifedipine elicited qualitatively similar effects, causing a dose-dependent decrease in blood pressure and systemic vascular resistance. These effects were accompanied by a reflex-mediated increase in heart rate, cardiac output and left ventricular rate of rise in pressure (LVdP/dtmax). Nisoldipine was about 2-3 times more potent than the other two drugs. Propranolol did not modify the vasodilation induced by the Ca2+ channel blockers but attenuated the increase in heart rate, cardiac output and LVdP/dtmax. In view of the reflex-tachycardia and the absence of negative inotropic actions, these Ca2+ channel blockers can be combined with beta-adrenoceptor antagonists without further compromising the left ventricular pump function.

Animals↗

PubMed1988

5-Hydroxytryptamine-induced tachycardia in the pig: possible involvement of a new type of 5-hydroxytryptamine receptor.

1. The mechanism of 5-hydroxytryptamine (5-HT)-induced tachycardia is species-dependent and is mediated directly or indirectly either by '5-HT1-like' (cat), 5-HT2 (rat, dog) or 5-HT3 (rabbit) receptors, or by an action similar to tyramine (guinea-pig). The present investigation is devoted to the analysis of the positive chronotropic effect of 5-HT in the pentobarbitone-anaesthetized pig. 2. Intravenous bolus injections of 5-HT (3, 10 and 30 micrograms kg-1) in pigs resulted in dose-dependent increases in heart rate of 24 +/- 2, 38 +/- 3 and 51 +/- 3 beats min-1, respectively (n = 39). Topical application of a high concentration of 5-HT (150 micrograms kg-1 in 5 ml) on the right atrium was also followed by tachycardia (38 +/- 6 beats min-1, n = 4). 3. A number of drugs which antagonize responses mediated by different 5-HT receptors--phenoxybenzamine, methiothepin, metergoline, methysergide and mesulergine ('5-HT1-like' and 5-HT2 receptors), ketanserin, cyproheptadine, pizotifen and mianserin (5-HT2 receptors), and MDL 72222 and ICS 205-930 (5-HT3 receptors)--did not attenuate the chronotropic responses to 5-HT. 4. The 5-HT-induced tachycardia was also not affected by antagonists at alpha- and beta-adrenoceptors, muscarinic, nicotinic, histamine and dopamine receptors, and calcium channels. 5. Selective inhibitors of 5-HT-uptake, indalpine and fluvoxamine, themselves increased porcine heart rate and facilitated 5-HT-induced tachycardia both in magnitude and in duration. 6. A number of putative selective agonists at '5-HT1-like' receptors or their possible subtypes (5- carboxamidotryptamine (5-CT), 8-hydroxy-24di-N,N-n-propylamino) tetralin (8-OH-DPAT), BEA 1654 and RU 24969), or at 5-HT3 receptors (2-methyl-5-HT), elicited no or only a weak tachycardiac response in the pig. RU 24969, but not 8-OH-DPAT, seemed to potentiate the responses to 5-HT, whereas 5-CT slightly inhibited these responses. 7. It was concluded that the tachycardia induced by 5-HT in the pig does not involve the receptors for some common neurotransmitter substances but may be mediated by a new 5-HT receptor type that is clearly different from '5-HT1-like', 5-HT2 or 5-HT3 receptors.

Animals↗

PubMed1988

Nisoldipine and perfusion of post-stenotic myocardium in conscious pigs with different degrees of concentric stenosis.

1. The effects of oral nisoldipine on the perfusion and wall function of a myocardial segment distal to a fixed coronary artery stenosis were studied in 2 groups of conscious pigs with different degrees of stenosis. In group 1 (n = 8) systolic wall thickening (SWT) of the post-stenotic segment was more than 15% (27 +/- 4%); in group 2 (n = 7) SWT was less than 10% (7 +/- 1%). 2. The systemic haemodynamic profiles at baseline and during nisoldipine were similar in both groups. Dose-titrations of nisoldipine (0.24 +/- 0.02 mg kg-1 and 0.47 +/- 0.04 mg kg-1) were performed to obtain increases in heart rate of 25% and 50%, respectively. These increases were accompanied by increases in cardiac output (up to 50%) and left ventricular (LV)dP/dt max (60%), while systemic vascular resistance (35%) and mean arterial blood pressure (10%) were reduced. Left ventricular systolic and end-diastolic blood pressure and stroke volume were not affected. 3. In both groups, nisoldipine caused increases in blood flow to the non-stenotic area which favoured the subepicardium more than the subendocardium. Blood flow to the post-stenotic area of group 1 was normal at baseline and was only slightly enhanced (preferentially to the subepicardium) by nisoldipine. In the post-stenotic area of group 2 transmural and subendocardial blood flow were lower at baseline compared to the control area. Nisoldipine did not affect subepicardial blood flow but reduced subendocardial blood flow. 4. In spite of the reflex-mediated positive chronotropic actions of nisoldipine, the acute poststenotic systolic wall thickening was not affected by nisoldipine in either group. 5. We conclude that, under the experimental conditions employed (concentric stenosis, no coronary collaterals and acute drug administration), nisoldipine does not have a useful effect on post-stenotic myocardial blood flow, particularly in animals with severe stenosis. In view of a possible resetting of the baroreceptors (subsiding of the tachycardia) with chronic treatment and the presence of eccentric stenosis in many patients, additional studies are warranted.

Animals↗

PubMed1987

Cardiovascular effects of UD-CG 212 CL, a metabolite of pimobendan, in anaesthetized pigs.

Systemic and regional haemodynamic effects of UD-CG 212 CL (0.5-16 micrograms X kg-1 X min-1), the major metabolite of the vasodilator and cardiotonic drug pimobendan, were studied in anaesthetized pigs. The drug caused a dose-dependent decrease in left ventricular (LV) end-diastolic and arterial blood pressures while it increased systemic vascular conductance, heart rate and maxLVdP/dt. The decrease in LV end-diastolic pressure was observed at lower plasma concentrations than the increase in systemic vascular conductance. Cardiac output tended to decrease but statistical significance was achieved only with the highest concentration. These effects of UD-CG 212 CL were not altered by the blockade of beta-adrenoceptors with propranolol. The vasodilator action of UD-CG 212 CL was noticed in several organs but the effects were relatively more marked (in decreasing order of magnitude) in the adrenals, kidneys, gastrointestinal tract, brain and LV epicardium. Since both arterial pressure and cardiac output decreased, the blood flow increased significantly only in the adrenals and decreased moderately in the spleen, LV endocardium and skeletal muscles. The effects of UD-CG 212 CL on the renal and skeletal muscle haemodynamics were different from those of pimobendan, which causes vasodilatation in the skeletal muscles but not in the kidneys. The results of this study show that, like the parent compound pimobendan, UD-CG 212 CL has independent cardiotonic and vasodilator actions; the latter being more pronounced on the venous side. However, the contribution of this metabolite to the overall pharmacological activity of pimobendan appears to be limited.

Adrenergic beta-Antagonists↗

PubMed1987

Enhancement of vasoconstrictor and attenuation of vasodilator effects of 5-hydroxytryptamine by the calcium channel blockers nimodipine and nifedipine in the pig.

As calcium (Ca2+) channel blockers are effective against the vasoconstrictor responses to 5-hydroxytryptamine (5-HT) in vitro, and a favourable response is claimed for these drugs in migraine prophylaxis, we studied the interaction between nimodipine or nifedipine, and 5-HT for effects on carotid haemodynamics in the anaesthetized pig. Intracarotid infusions of nimodipine (0.25 microgram X kg-1 X min-1), nifedipine (0.75 microgram X kg-1 X min-1) or 5-HT (2.0 micrograms X kg-1 X min-1) caused a redistribution of carotid blood flow in favour of the nutrient (capillary) fraction at the expense of the non-nutrient (arteriovenous anastomoses; AVA) fraction. Compared to those of 5-HT, the effects of the Ca2+ channel blockers on cranial AVAs were much weaker and the increase in the capillary fraction was observed mainly in the skeletal muscles, rather than in the skin and ears as with 5-HT. When 5-HT was infused in the presence of nimodipine or nifedipine, the amine-induced vasoconstrictor responses in the total carotid vascular bed and its AVA fraction were either not attenuated or were increased while the vasodilator responses were reduced. We conclude that: in contrast to what was found in vitro, the 5-HT-induced vasoconstriction in vivo, involving either '5-HT1-like' (AVAs) or 5-HT2 (arterioles) receptors, was not antagonized by nimodipine or nifedipine; the attenuation of the 5-HT-induced dermal vasodilatation by the two Ca2+ channel blockers is most likely to be the result of a 'steal' due to the profound vasodilatation in the skeletal muscle region; and the comparatively mild reduction in AVA conductance caused by the Ca2+ channel blockers may be one of the reasons for their inability to abort acute attacks of migraine. The increase in nutrient blood flow is of potential benefit, but whether this property of the Ca2+ channel blockers is linked to their usefulness in migraine prophylaxis remains to be ascertained.

Animals↗

PubMed1987

Nicorandil-induced changes in the distribution of cardiac output and coronary blood flow in pigs.

The present investigation was conducted to study systemic and regional haemodynamic effects of nicorandil, a potent coronary vasodilator, after intravenous or local intracoronary administration in anaesthetized or conscious pigs. Intravenous infusions of nicorandil for 10 min in both anaesthetized (15, 30, 75 and 150 micrograms.kg-1.min-1) and conscious (20, 40 and 80 micrograms.kg-1.min-1) pigs reduced arterial blood pressure, stroke volume, left ventricular end-diastolic pressure (LVEDP) and systemic vascular resistance, but increased heart rate and maxLVdP/dt. Since nicorandil decreased LVEDP at doses which did not affect arterial blood pressure, the drug may be considered as a more potent venodilator than arterial dilator. Nicorandil increased cardiac output only in conscious animals due to a more marked tachycardia (85% after 80 micrograms.kg-1.min-1) than in anaesthetized animals (30% after 75 micrograms.kg-1.min-1). The nicorandil-induced increase in heart rate and maxLVdP/dt, being substantially attenuated in conscious pigs after treatment with propranolol, can be ascribed to a reflex activation of the sympathetic nervous system following the fall in arterial pressure. Although cardiac output did not change in anaesthetized animals, intravenous infusions of nicorandil did cause a redistribution of blood flow in favour of organs such as the heart, adrenals, spleen, small intestine and brain at the expense of that to the stomach and kidneys; hepatic artery and skeletal muscle blood flow did not change. The increase in myocardial blood flow, primarily to the subepicardial layers, was associated with an enhancement in coronary venous oxygen content and was also notices after intracoronary infusions of nicorandil (0.6, 1.5, 3 and 6 micrograms.kg-1.min-1).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1987

Changes in systemic haemodynamics, regional myocardial function and perfusion induced by alinidine in pigs with and without narrowed coronary arteries.

Intravenous administration of 0.2-6.0 mg kg-1 of alinidine, an N-allyl derivative of clonidine, exerted a pronounced bradycardic action and also decreased the maximum rate of rise in left ventricular pressure (max LVdP/dt), cardiac output, and mean arterial blood pressure in anaesthetized as well as in conscious pigs. When, in the anaesthetized animals, heart rate was kept constant by atrial pacing, no changes were observed with alinidine in maxLVdP/dt and cardiac output at doses up to 0.4 mg kg-1. At higher doses, however, there was a significant reduction in these variables, demonstrating a marked negative inotropic action of the drug at higher concentrations. In pigs with normal hearts alinidine homogeneously reduced myocardial perfusion, but no imbalance in the myocardial oxygen supply-demand relationship was noticed due to a simultaneous reduction of the metabolic needs of the myocardium. After constriction of the left anterior descending coronary artery to an extent that systolic myocardial wall thickening was reduced to 30% of its base-line value, transmural myocardial blood flow and the endocardial-epicardial (endo-epi) ratio in the affected myocardial segment had decreased from 1.42 +/- 0.15 to 0.68 +/- 0.11 ml min-1 g-1 and from 1.05 +/- 0.08 to 0.59 +/- 0.10, respectively. Though myocardial blood flow in the normal segments decreased, alinidine, in a dose (0.4-0.9 mg kg-1) that lowered heart rate by about 25%, caused a redistribution of blood flow to the ischaemic myocardium in favour of the endocardium as the endo-epi ratio increased to 1.08 +/- 0.12. Concomitantly, systolic wall thickening of the hypokinetic segment returned to 50% of its base-line value. Thus, alinidine ameliorated the imbalance between oxygen supply and demand in the post-stenotic myocardial segment, probably by prolongation of the diastolic perfusion time and a diminution in myocardial oxygen demand both through a reduction in heart rate. However, other factors, such as negative inotropy may also have partly contributed. Since treatment of pathological cardiovascular conditions with drugs with positive inotropic and vasodilatory properties is often accompanied by tachycardia, we also studied the effects alinidine in combination with the phosphodiesterase inhibitor sulmazole. Alinidine did not interfere with the positive inotropic and vasodilatory (systemic as well as coronary) properties of sulmazole, but prevented the tachycardia. These data suggest that combination of negative chronotropic drugs as alinidine with agents with a cardiovascular profile similar to sulmazole may be attractive, when unwanted tachycardia occurs.

Animals↗

PubMed1987

Changes in regional blood flows and myocardial performance after administration of bisoprolol to pigs.

The cardioselective beta-adrenoceptor antagonist bisoprolol (4-1024 micrograms kg-1) caused in anaesthetized open-chest pigs a dose-dependent decrease in cardiac output, which was primarily due to a negative chronotropic action as heart rate decreased more than stroke volume. The decrease in stroke volume apparently resulted from a negative inotropic action of the drug, reflected by a decrease in max LV dP/dt in animals both with and without atrial pacing. A mild increase in systemic vascular resistance prevented serious hypotension. Pulmonary artery pressure was not affected, as pulmonary vascular resistance increased although the increase was statistically significant only with the highest concentration. The dose-related decreases in left ventricular blood flow were equally distributed over all myocardial layers and were the consequence of the reduced metabolic needs of the myocardium. Cerebral blood flow was well preserved but the changes in blood flow to some other organs and tissues (kidneys, stomach and skeletal muscle) paralleled that in cardiac output. The systemic haemodynamic effects of bisoprolol (16-1024 micrograms kg-1; i.v.) in conscious pigs resembled closely those observed in anaesthetised animals and were similar to those exerted by propanolol (25-300 micrograms kg-1; i.v.) in the same preparation. The effectiveness of bisoprolol and propranolol in antagonizing isoprenaline-induced changes in heart rate and max LV dP/dt were, however, markedly different. While propranolol inhibited both parameters to the same extent, bisoprolol was more effective in inhibiting max LV dP/dt than heart rate responses in conscious animals, probably due to beta 1-adrenoceptor selectivity.

Adrenergic beta-Antagonists↗

PubMed1987

The effects of nisoldipine alone and in combination with beta-adrenoceptor blockade on systemic haemodynamics and myocardial performance in conscious pigs.

The peak effects of 10 mg nisoldipine p.o. with or without 80 mg propranolol p.o. on systemic and regional haemodynamics in conscious pigs were investigated. Nisoldipine increased heart rate (70%), cardiac output (67%) and maxLVdP/dt (75%), but decreased mean arterial pressure (21%) as systemic vascular conductance increased by 120%. Left ventricular systolic and end-diastolic pressures were not affected. Vasodilatation occurred in most organs. The increase in left ventricular blood flow (150%) favoured the epicardial (195%) over the endocardial (110%) layers. As a result the endo-epi blood flow ratio decreased by 30%. When nisoldipine was administered simultaneously with propranolol, heart rate (29%), cardiac output (35%) and systemic vascular conductance (65%) increased, but maxLVdP/dt did not change. Mean arterial (18%) and left ventricular systolic (10%) pressure decreased; left ventricular end-diastolic pressure was again unaffected. In most organs vasodilatation was attenuated, but still present, compared to the changes after nisoldipine alone. The increase in epicardial blood flow (70%) again exceeded that in endocardial blood flow (35%), however, the endo-epi ratio decreased by only 15%. In the presence of propranolol, nisoldipine did not exert a negative inotropic action while the reflex-tachycardia was attenuated. In addition, no detrimental effects on perfusion of regional vascular beds were observed.

Animals↗

PubMed1987

Systemic haemodynamic actions of pimobendan (UD-CG 115 BS) and its O-demethylmetabolite UD-CG 212 Cl in the conscious pig.

The cardiovascular effects of the pyridazinone-derivatives pimobendan and its O-demethylmetabolite UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4,5-dihydro-2H-6-pyridazinyl) benzimidazole HCl) were studied in conscious pigs, employing consecutive intravenous 10 min infusions of 10, 25, 50 and 100 micrograms kg-1 min-1 and 2, 4 and 8 micrograms kg-1 min-1 respectively. Pimobendan caused dose-dependent increases in LVdP/dtmax (up to 115%) and heart rate (up to 30%), while cardiac output was slightly elevated (up to 15%) and stroke volume decreased by 12%. Left ventricular end-diastolic pressure decreased in a dose-related manner from 8.7 +/- 1.0 mmHg to 2.7 +/- 1.7 mmHg. Mean arterial blood pressure was not significantly affected because systemic vascular resistance decreased dose-dependently up to 15%. After beta-adrenoceptor blockade, the pimobendan-induced increases in heart rate and cardiac output were attenuated and the increase in LVdP/dtmax almost abolished. The responses of left ventricular end-diastolic and mean arterial blood pressure, systemic vascular resistance and stroke volume were not modified. UD-CG 212 Cl caused dose-related increases in LVdP/dtmax (up to 100%) and heart rate (up to 25%). Cardiac output was minimally elevated (up to 8%) as stroke volume decreased dose-dependently up to 15%. As systemic vascular resistance decreased up to 12%, mean arterial blood pressure was slightly reduced (5%). Left ventricular end-diastolic blood pressure decreased dose-dependently from 9.0 +/- 0.8 mmHg to 3.8 +/- 1.3 mmHg. After beta-adrenoceptor blockade, the UD-CG 212 Cl-induced increases in heart rate and LVdP/dtmax were attenuated and almost abolished and amounted up to 15% and 20%, respectively. The responses of the other systemic haemodynamic parameters were not significantly modified. We conclude that pimobendan and UD-CG 212 Cl are compounds with marked positive inotropic and venodilator properties in the conscious pig. The attenuation of the inotropic effects by pretreatment with propranolol strongly suggests that, in the conscious pig, the beta-adrenergic system is significantly involved in the positive inotropic actions. The lack of effect of beta-adrenoceptor blockade on the vasodilator responses to both compounds suggest a mechanism not related to beta-adrenergic activity.

Animals↗

PubMed1987

Systemic haemodynamic and beta-adrenoceptor antagonistic effects of bisoprolol in conscious pigs: a comparison with propranolol.

We studied the cardiovascular profile of the new cardioselective beta-adrenoceptor antagonist bisoprolol in the conscious pig and compared this profile with that of propranolol. Acute i.v. administration of bisoprolol (16-1024 micrograms.kg-1) did not affect mean arterial blood pressure but caused dose-related decreases in cardiac output (from 8 to 17%; p less than 0.05) due to a negative chronotropic action (heart rate reduction ranging from 9 to 21%; p less than 0.05) as stroke volume was unaffected. Max LVdP/dt decreased (ranging from 18 to 27%; p less than 0.05) while left ventricular end-diastolic blood pressure (from 8.6 +/- 0.6 to 15 +/- 0.2 mmHg; p less than 0.05) and systemic vascular resistance (from 8 to 18%; p less than 0.05) increased. Propranolol in a dose-range from 25-300 micrograms.kg-1 produced strikingly similar changes. Bisoprolol was more effective in antagonizing the isoproterenol-induced responses of max LVdP/dt than those on either heart rate or diastolic arterial blood pressure, whereas propranolol caused equi-effective inhibitions of the responses of heart rate and max LVdP/dt. However, with propranolol also the inhibition of the diastolic arterial blood pressure was less marked than for the other parameters. Propranolol proved to be the more potent beta-adrenoceptor antagonist, as the isoproterenol dose ratios of all 3 parameters during beta-adrenoceptors blockade with propranolol exceeded those obtained with bisoprolol.

Adrenergic beta-Antagonists↗

PubMed1986

Cardiovascular profile of pimobendan, a benzimidazole-pyridazinone derivative with vasodilating and inotropic properties.

Intravenous infusions of 0.01-0.1 mg X kg-1 X min-1 of pimobendan, a benzimidazole-pyridazinone derivative in pigs with normal coronary circulation caused dose-dependent changes in heart rate (10-35%), left ventricular systolic pressure (-5 to -45%), left ventricular filling pressure (-20 to -40%) but had only a minor effect on the maximum rate of rise of left ventricular pressure (max LVdP/dt; 10-20%). The decrease in mean arterial blood pressure was primarily due to systemic vasodilation; peripheral resistance and cardiac output decreased by up to 40 and 14%, respectively. Vasodilation occurred in several vascular beds, but was particularly pronounced in the adrenals, stomach, small intestine and myocardium. Although the increase in myocardial blood flow favoured the epicardium, vascular conductance in both the endo- and epicardial layers was significantly increased. Myocardial O2 consumption (MVO2) was not affected despite the increase in heart rate. Bolus injections of 0.1-0.5 mg X kg-1 pimobendan produced similar changes in all haemodynamic variables, except max LVdP/dt which now increased by 30-70%. As in the infusion experiments, cardiac output tended to decrease due to a pronounced reduction in ventricular preload probably as a result of venodilation and the consequent reduction in cardiac filling. However, in animals where max LVdP/dt and cardiac output were reduced and pre- and/or after-load were increased by partial occlusion of the left anterior descending coronary artery, pimobendan clearly increased both max LVdP/dt and cardiac output. Pretreatment with propranolol did not modify any of the cardiovascular responses to pimobendan, thereby excluding the involvement of a beta-adrenoceptor mechanism. Pimobendan is thus a compound with vasodilator and positive inotropic properties that improves cardiac output in animals with severe myocardial ischaemia. The finding that the mild tachycardia caused by pimobendan was not accompanied by an increase in MVO2 warrants investigation to evaluate its usefulness in the treatment of heart failure.

Adrenergic beta-Antagonists↗

PubMed1986

Effects of MDL 72222 and methiothepin on carotid vascular responses to 5-hydroxytryptamine in the pig: evidence for the presence of "5-hydroxytryptamine1-like" receptors.

The present study concerns the effects of MDL 72222 (0.5 mg X kg-1, i.v.), a 5-hydroxytryptamine3 (5-HT3) receptor antagonist, and methiothepin (1.0 mg X kg-1, i.v.), an antagonist of both 5-HT2 and "5-HT1-like" receptors, on the responses to local infusions of 5-HT (2.0 micrograms X kg-1 X min-1) on the total common carotid artery blood flow and its complete distribution in anaesthetized pigs. As reported earlier, more than 80% of the carotid blood bypassed the capillary circulation via cranial arteriovenous anastomoses, while approximately 15% and 2% was distributed to the extracerebral structures and brain, respectively. The total carotid blood flow did not change or was moderately reduced by 5-HT, but the amine consistently caused a 85% reduction in arteriovenous anastomotic blood flow and a 5-fold increase in blood flow to the extracerebral tissues, mainly the skin and ears. The colour of the skin and ears changed to bright pink. Complete recovery from the effects of 5-HT was observed once the infusion was stopped. MDL 72222 and methiothepin did not themselves affect carotid haemodynamics. The responses to 5-HT were not modified by MDL 72222 except that the reduction of the total carotid blood flow by 5-HT was augmented. In contrast, methiothepin almost completely abolished both the reduction of arteriovenous anastomotic blood flow and the increase in tissue blood flow following 5-HT-infusion. The colour of the skin and ears also did not become pink.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1986

The effects of nisoldipine (Bay K 5552) on cardiovascular performance and regional blood flow in pentobarbital-anaesthetized pigs with or without beta-adrenoceptor blockade.

The effects of the 1,4-dihydropyridine derivative nisoldipine, infused intravenously (i.v.) at 3 different rates (0.25, 0.5 and 1.0 microgram kg-1 min-1), were studied in anaesthetized pigs on cardiovascular performance with or without beta-adrenoceptor blockade produced by propranolol. Nisoldipine caused dose-dependent decreases in arterial blood pressure (30%), systemic vascular resistance (30%) and left ventricular filling pressure (15%), but raised heart rate (25%) and LV dP/dt max (20%). Cardiac output was not significantly affected. Transmural myocardial blood flow and vascular conductances increased dose-dependently after nisoldipine. The elevation in blood flow to the left ventricle favoured epicardial layers. Endocardial blood flow showed small increases as the changes in conductance of the endocardial layer more than compensated for the loss in perfusion pressure. The endo-epi blood flow ratio decreased from 1.16 +/- 0.05 to 0.70 +/- 0.01. Myocardial O2-consumption was unaltered as the decrease in arterial-coronary venous O2-content difference (30%) was balanced by the increase in transmural blood flow. Nisoldipine increased blood flow to skeletal muscle (500%), stomach (50%) and adrenals (25%), but decreased that to the liver (50%), spleen (25%) and kidneys (25%). No changes were noticed in the small intestine, skin and brain. In spite of differential effects on blood flow, vascular conductance in all organs and tissues, with the exception of the liver, increased. After beta-adrenoceptor blockade the responses of mean arterial blood pressure, cardiac output and systemic vascular resistance to nisoldipine remained virtually unchanged, but the elevations in heart rate and LV dP/dt max were abolished, as was the decrease in left ventricular filling pressure. A higher dose of nisoldipine was required after beta-adrenoceptor blockade to elicit significant vasodilatation in the epi- and endocardial layers. However, the reduction in endo-epi blood flow ratio by nisoldipine was not affected by propranolol. Myocardial O2-consumption tended to decrease as the diminution in the arterial-coronary venous O2-content difference (30%) slightly exceeded the increase of left ventricular blood flow (30%). Except for the brain and liver, effects of nisoldipine on regional vascular conductances were attenuated after beta-adrenoceptor blockade.

Adrenergic beta-Antagonists↗

PubMed1986

Nimodipine-induced changes in the distribution of carotid blood flow and cardiac output in pentobarbitone-anaesthetized pigs.

In view of the claimed effectiveness of nimodipine in migraine and its possible selectivity for cerebral vessels, we investigated the effects of nimodipine in anaesthetized pigs on the fractionation of carotid arterial blood flow into non-nutrient (arteriovenous anastomoses; AVAs) and nutrient (capillary) parts, and on regional tissue blood flows and vascular conductances. Intracarotid infusions of nimodipine (0.05-1.25 microgram kg-1 min-1) redistributed carotid blood flow in favour of its nutrient compartment, particularly to the skeletal muscles and tongue. Vascular conductance in the non-nutrient (AVAs) compartment decreased (40%), most likely, as a result of 'steal' following profound (5.5 fold) arteriolar dilatation. Intravenous infusions of nimodipine (0.05-6.25 micrograms kg-1 min-1) caused hypotension, bradycardia, a decrease in conduction in the non-nutrient fraction, and an increase in conduction in the nutrient fraction (mostly in the skeletal muscles, but also in the gastrointestinal tract, cerebral hemispheres, heart and adrenals). Probably due to the hypotensive effect, only skeletal muscle blood flow increased. The nimodipine-induced increase in vascular conductance in the skeletal muscles showed regional variation; the effect was most pronounced in the cheek muscles, followed by the muscles of the chest, abdominal, trunk and gluteal regions. We conclude that: AVA flow seems to represent a 'reserve' perfusion which can be readily diverted to tissues in the case of increased metabolism and/or vasodilatation, though the overall response to nimodipine of carotid blood flow distribution qualitatively resembles that to some antimigraine drugs, the relevance of such acute effects in the prophylactic usefulness of nimodipine in migraine remains to be ascertained, and nimodipine lacks a selective cerebral vasodilator action in the anaesthetized pig.

Anesthesia↗