ABSTRACT
In this study, we report the existence of a communication system among human smooth muscle cells that uses mechanical forces to frequency modulate long-range calcium waves. An important consequence of this mechanical signaling is that changes in stiffness of the underlying extracellular matrix can interfere with the frequency modulation of Ca2+ waves, causing smooth muscle cells from healthy human donors to falsely perceive a much higher agonist dose than they actually received. This aberrant sensing of contractile agonist dose on stiffer matrices is completely absent in isolated smooth muscle cells, although the isolated cells can sense matrix rigidity. We show that the intercellular communication that enables this collective Ca2+ response in smooth muscle cells does not involve transport across gap junctions or extracellular diffusion of signaling molecules. Instead, our data support a collective model in which mechanical signaling among smooth muscle cells regulates their response to contractile agonists.
ABSTRACT
The combined use of some beta-adrenoceptor blocking agents with calcium channel blockers may cause adverse pharmacodynamic drug interactions: hypotension, heart block or even asystole may be precipitated. The electrophysiological effects of combined administration of intravenous metoprolol 10mg and the vasodilating calcium antagonist felodipine (0.1 mg/kg/bodyweight) were assessed in an open study by invasive methods. Following metoprolol, the heart rate was reduced from 69 +/- 24 to 60 +/- 16 beats/min (mean +/- SD, p less than 0.05) with a minor prolongation of the sinus node recovery time. The A-H interval was increased from 94 +/- 25 to 109 +/- 16 msec (p less than 0.005) and the H-V interval was unchanged. The effective refractory period of the atrioventricular node was prolonged from 327 +/- 54 to 361 +/- 62 msec (p less than 0.01) with a minor prolongation of the effective refractory period of the ventricular Purkinje fibres. Systolic and diastolic blood pressures showed a mean reduction of 11 (p less than 0.001) and 6mm Hg (p less than 0.05), respectively. Following felodipine, the changes in heart rate and effective refractory periods of the atrioventricular node and ventricular Purkinje fibres returned towards control values. No further prolongation of the A-H interval resulted and further blood pressure changes were minor. The absence of adverse haemodynamic or electrophysiological effects suggests that this combination of agents may be safely used.
