The effect of the cardiac swelling-induced chloride current (I(Cl,swell)) on the transmembrane potential was examined. Osmotic swelling affected the resting potassium current through an apparent dilution of intracellular potassium. Inflating cells by applying positive pressure to the patch electrode prevented the effect on the resting potassium current. Inflation depolarized dog atrial myocytes when the recording electrodes contained either 17 or 42 mM Cl-. The depolarization coincided with activation of I(Cl,swell) and was antagonized by the chloride-channel blocker niflumic acid. Substituting extracellular chloride with the more permeant ion SCN- shifted the reversal potential for I(Cl,swell) to more negative values and antagonized inflation-induced depolarization. The depolarization was accentuated by replacing extracellular chloride with a less permeant ion, aspartate. We conclude that activation of I(Cl,swell) in atrial cells causes significant depolarization of the resting membrane. The outward rectification of I(Cl,swell) and the high cell membrane resistance during the action potential plateau suggest that I(Cl,swell) will also have significant effects on atrial action potential configuration.

Positive chronotropic as well as inotropic effects of 5-hydroxytryptamine (5-HT) have been observed in pig atrial tissue, but no data are available about the direct effects of 5-HT on ventricular tissue. In the present study we investigated inotropic effects of 5-HT on atrial and ventricular trabeculae obtained from hearts of 3 months old pigs. The baseline isometric contractile force was significantly higher in ventricular (4.14 +/- 1.25 mN) than in atrial tissue (0.47 +/- 0.11 mN). A noradrenaline concentration-response curve (0.01 to 10 mumol/l) was used to check contractile responsiveness of the tissue and all responses were expressed as percentage of the response to 10 mumol/l noradrenaline. Noradrenaline caused a concentration-dependent increase in contractile force in both atrial and ventricular trabeculae. In contrast, though 5-HT (0.01 to 100 mumol/l) did increase force of contraction in atrial tissue (maximum: 72 +/- 20% of the response to noradrenaline 10 mumol/l), the contractility of ventricular trabeculae was not significantly affected (maximum: 12 +/- 6%). The present data show that, in contrast to atrial tissue, contractile force of ventricular tissue could not be significantly affected by 5-HT. To our knowledge, this is the first study to show that an agent which increased force of contraction in the atrium, did not have a corresponding effect on the ventricle. These findings may have important implications for a better understanding of the physiology and pharmacology of cardiac contractility.

Cardiac swelling-induced chloride current activates with a distinct lag after step changes in cell size. The activation time course is temperature sensitive. These observations are consistent with the notion that signal transduction events, and not simply membrane stretch, are required for the activation of cardiac swelling-induced chloride current.

The sensory neuropeptide, calcitonin gene-related peptide (alpha-CGRP), has been implicated in the pathogenesis of migraine headache. The present study aimed to evaluate the effects of intracarotid infusions of human alpha-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 micrograms/kg i.v.; n = 4) or sumatriptan (300 micrograms/kg i.v.; n = 4), on these parameters were studied in the presence of the infusion of the highest concentration of human alpha-CGRP. Additionally, putative positive inotropic responses to human alpha-CGRP (10(-9)-10(-7) M) were investigated in porcine isolated atrial and ventricular trabeculae. Human alpha-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 dihydroergotamine 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 alpha-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 alpha-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 (approximately 25% of the response to 10(-5) M noradrenaline, n = 10). These data indicate that human alpha-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 alpha-CGRP in the porcine carotid circulation.

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