Pharmacology of the human and porcine isolated myocardium

The heart, an important organ of the mammalian, operates as a pump. It is composed of two pumps: the right heart pumps the blood through the lungs while the left heart pumps the blood through peripheral organs. In turn, each of these separate pumps are composed of two pulsatile chambers, an atrium and a ventricle. Each minute, the heart of a resting adult pumps about 5 L of blood, or approximately the person's total blood volume. This works out to at least 720 Ll a day, the volume of blood weighting about 100 times more than the body. This heavy and incessant work is based on the fact that the heart muscle has a coordinated contraction. The cardiac muscle fibres are highly organized with strong inter-connections. A trigger pulse from the sinoatrial node, being the pacemaker, initiates and coordinates contraction, making possible the function of the heart as a pump and the contractility as the major parameter of the function of the heart

Different pharmacological responses of atrium and ventricle: Studies with human cardiac tissue

It has been recently reported that 5-hydroxytryptamine (5-HT) increases force of contraction in atrial tissue but not in ventricular tissue. In the present study with trabeculae obtained from non-diseased human hearts, we investigated whether this difference in the contractile response is specific for 5-HT or is also observed for other substances: calcitonin gene-related peptide (CGRP), angiotensin II, adenosine, somatostatin and acetyllcholine. CGRP (10−9 to 10−7 M) and angiotensin II (10−9 to 10−5 M) caused concentration-dependent increases in force of contraction in atrial trabeculae (up to36 ± 8%and42 ± 8% of the response to 10−5 M noradrenaline, respectively). Similar to 5-HT, no effects were observed with CGRP and angiotensin II in ventricular trabeculae. Adenosine (10−8 to 10−5 M) and somatostatin (10−8 to 10−6 M) caused concentration-dependent negative inotropic effects on baseline atrial contractility (−54 ± 17%and−51 ± 25%, respectively, but no response was found on baseline ventricular contractility. Adenosine, but not somatostatin, reduced force of contraction after pre-stimulation with 10−5 M noradrenaline in atrial tissue and, to a lesser extent, in ventricular tissue. Acethlcholine exhibited a biphasic concentration-response curve in the atrial tissue, consisting of an initial negative inotropic response (10−9 to 10−7 M, from 120 ± 41mg at baseline to48 ± 16mg at 10 −7 M, fol lowed by a positive inotropic response (10−6 to 10−3 M, from 48 ± 16 mg at 10−7 M to77 ± 55mg). On the baseline ventricular for foce of contraction, acetylcholine (10−9 to 10−4 M) induced only a positive inotropic effect, starting at 10−9 M (from 252 ± 65mg at baseline to353 ± 71mg at 10−4M). After pre-stimulation with 10−5 M noradrenaline, acethylcholine reduced force of contraction in both tissue at 10−3 M(atrium: −14 ± 4%,ventricle: −61 ± 5%). The data indicate that, in atrial tissue, force of contraction can be affected by either postive or negative inotropic agents. However, in ventricular tissue only positive inotropic effects could be detected. Since atrial and ventricular tissues display different responses to the above biogenic substances, a different mechnism of regulation of contractility seems feasible

Characterization of the positive and negative inotropic effects of acetylcholine in the human myocardium

In the human isolated myocardium, acetylcholine (10−9 to 10−3 M) elicited a biphasic inotropic effect (a decrease in the lower and an increase in the higher concentration range) in atrial and a positive inotropic effect in ventricular trabeculae. However, under conditions of raised contractility achieved by exposure to noradrenaline (10−5 M), only negative inotropic effects were observed in both atria and ventricles. Atropine (10−6 M), but not propranolol (10−6 M), antagonized both positive and negative inotropic effects of acetylcholine, thus showing that the responses were mediated by muscarinic acetylcholine receptors. The use of subtype selective muscarinic receptor antagonists (10−7 to 10−5 M), pirenzepine (M1 > M3 > M2), AF-DX 116 (11-({2-[(diethylamino)-methyl]-1-piperidyl}acetyl)-5,11-dihydro-6H-pyridol[2,3-b][1,4]benzodiazepine-6-one base; M2 > M1 > M and HHSiD (p-fluorohexahydro-siladifenidol hydrochloride; M3 ≥ M1 ⪢ M2) revealed that the negative inotropic effect of acetylcholine in atrial as well as the positive inotropic effect in ventricular trabeculae were best antagonized by AF-DX 116 and not by pirenzepine, suggesting the involvement of the muscarinic M2 receptor subtype, possibly linked to different second messenger systems. On the other hand, the positive inotropic effect of acetylcholine (10−6 to 10−3 M) in the atrial tissue, observed only in preparation with depressed contractility, was not effectively antagonized by either AF-DX 116 or HHSiD, but was significantly reduced by pirenzepine. Furthermore, the selective muscarinic M1 receptor agonist McN-A-343 (4-(m-chlorophenylcarbamoyloxy)-2-butynyltrimethyl ammonium chloride; 10−9 to 10−3 M), which failed to significantly change the baseline contractility in either atrial or ventricular trabeculae, produced a positive inotropic effect in atrial preparations when contractility had been depressed by prior treatment with acetylcholine (10−9 to 10−7 M). This effect of McN-A-343 was effectively antagonized by pirenzepine (10−5 M). These data show that, besides the muscarinic M2 receptor mediating both negative (atria) and positive (ventricle) inotropic effects, muscarinic M1 receptors, capable of reversing depressed atrial contractility, are present in the human heart

Carotid blood flow distribution, haemodynamics and inotropic responses following calcitonin gene-related peptide in the pig

The sensory neuropeptide, calcitonin gene-related peptide (α-CGRP), has been implicated in the pathogenesis of migraine headache. The present study aimed to evaluate the effects of intracarotid infusions of human α-CGRP (10, 30 and 100 pmol/kg · min; n = 8), as compared to that of saline (4 times; n = 8) on haemodynamics and blood flow distribution within the carotid circulation of the anaesthetized pig, using the radioactive microsphere method. Furthermore, the effects of antimigraine drugs, dihydroergotamine (100 μg/kg i.v; n = 4) or sumatriptan (300 μg/kg i.v.; n = 4), on these parameters were studied in the presence of the infusion of the highest concentration of human α-CGRP. Additionally, putative positive inotropic responses to human α-CGRP (10−9–10−7 M) were investigated in porcine isolated atrial and ventricular trabeculae. Human α-CGRP increased carotid artery blood flow and conductance dose-dependently, together with an enhancement in vascular pulsations. These effects were associated with a fall in systemic blood pressure with concomitant increases in heart rate and cardiac output. The increase in carotid blood flow was reflected by an increase in total capillary blood flow, predominantly to extracerebral tissues including the dura, whereas blood flow through arteriovenous anastomoses remained stable. Both dihydroerogtamine and sumatriptan reduced carotid blood flow and its capillary fraction without affecting systemic vascular conductance. In tissues, these drugs reversed blood flow increases due to human α-CGRP in most extracerebral tissues, but failed to reduce dural blood flow. In porcine isolated atrial and ventricular trabeculae, noradrenaline (10−8–10−5 M) increased force of contraction in a concentration-dependent manner. In contrast, human α-CGRP (10−9–10−7 M) failed to increase force of contraction in atrial trabeculae (n = 6) and exerted only a moderate concentration-dependent positive inotropic effect in ventricular trabeculae (∼ 25% of the response to 10−5 M noradrenaline, n = 10). These data indicate that human α-CGRP caused arteriolar dilatation together with a fall in blood pressure in the pig. The tachycardia may be reflex-mediated, but the peptide also exerts a moderate positive inotropic action on ventricular trabeculae. The fall in systemic arterial blood pressure and the marked increase in capillary blood flow most likely prevented the opening of arteriovenous anastomoses. Furthermore, the antimigraine drugs, dihydroergotamine and sumatriptan, were able to reverse blood flow changes induced by human α-CGRP in the porcine carotid circulation