A pharmacologic activator of endothelial KCa channels increases systemic conductance and reduces arterial pressure in an anesthetized pig model

Abstract

SKA-31, an activator of endothelial KCa2.3 and KCa3.1 channels, reduces systemic blood pressure in mice and dogs, however, its effects in larger mammals are not well known. We therefore examined the hemodynamic effects of SKA-31, along with sodium nitroprusside (SNP), in anesthetized, juvenile male domestic pigs. Experimentally, continuous measurements of left ventricular (LV), aortic and inferior vena cava (IVC) pressures, along with flows in the ascending aorta, carotid artery, left anterior descending coronary artery and renal artery, were performed during acute administration of SKA-31 (0.1, 0.3, 1.0, 3.0 and 5.0mg/ml/kg) and a single dose of SNP (5.0 μg/ml/kg). SKA-31 dose-dependently reduced mean aortic pressure (mPAO), with the highest dose decreasing mPAO to a similar extent as SNP (-23 ± 3 and -28 ± 4 mmHg, respectively). IVC pressure did not change. Systemic conductance and conductance in coronary and carotid arteries increased in response to SKA-31 and SNP, but renal artery conductance was unaffected. There was no change in either LV stroke volume (SV) or heart rate (versus the preceding control) for any infusion. With no change in SV, drug-evoked decreases in LV stroke work (SW) were attributed to reductions in mPAO (SW vs. mPAO, r(2)=0.82, P<0.001). In summary, SKA-31 dose-dependently reduced mPAO by increasing systemic and arterial conductances. Primary reductions in mPAO by SKA-31 largely account for associated decreases in SW, implying that SKA-31 does not directly impair cardiac contractility.

Keywords: Blood pressure; Conductance; Endothelium; Hemodynamics; KCa channel.

Figure 1

Representative data from one pig demonstrating the rapid and reversible effects of SKA-31 and sodium nitroprusside (SNP) following acute intravenous infusion on mean aortic pressure (mP_AO) (panel A), systemic vascular conductance (panel B), measured conductance in coronary, carotid and renal arteries (panel C) and heart rate (panel D). In each panel, the sections of continuous data points displayed represent 5-min epochs that were extracted from the master data record and illustrate the basal levels and evoked changes in the measured parameters in response to the infusions. The horizontal bars and labels provided beneath each panel specify the experimental infusion for the 5-min section of data appearing immediately above each description. Note that all displayed data were acquired simultaneously during the experiment. Individual infusions were separated by a 15–20 min recovery period (indicated by the breaks between the sections of data points) and control hemodynamic data were acquired for the first 1–2 min period immediately prior to a given infusion, once a steady baseline was clearly apparent (not shown).

Figure 2

Quantification of mean aortic pressure (mP_AO) under control conditions and following acute infusion of SKA-31 (0.1 – 5.0 mg/ml/kg) and SNP (5.0 μg/ml/kg) (panel A). Panel B quantifies the drug-evoked changes in mP_AO relative to the preceding control value for each experimental condition. N = 7 animals for both panels A and B.

Figure 3

Quantification of the time to maximal change in mean aortic pressure (mP_AO) following intravenous infusion of either SKA-31 (0.1 – 5.0 mg/ml/kg) or SNP (5.0 μg/ml/kg). Administration of either saline or drug vehicle did not evoke measurable changes in mP_AO. The response evoked by 5.0 mg/ml/kg SKA-31 was significantly faster than that elicited by SNP, as determined by two-way ANOVA; P < 0.05, n = 7 animals.

Figure 4

Lack of effect of SKA-31 (0.1 – 5.0 mg/ml/kg) on mean inferior vena cava pressure (mP_IVC) following acute administration. Histogram displays mP_IVC values recorded in response to infusions of saline, drug vehicle and the indicated dosages of SKA-31 and SNP. Values for baseline mP_IVC (control) immediately preceding each infusion are designated by the black bars.

Figure 5

Acute administration of SKA-31 and sodium nitroprusside (SNP) reduce systemic vascular resistance (SVR). Panel A displays absolute values for SVR recorded prior to a given drug infusion and following SKA-31 and SNP infusions at the indicated dosages. For the latter data, measurements were taken during the peak change in SVR. Panel B displays the calculated percentage change in systemic vascular resistance under each infusion condition compared with the preceding control.

Figure 6

Quantification of evoked changes in arterial conductance calculated for the carotid, coronary and renal arteries in response to infusions of saline, drug vehicle, SKA-31 (0.1 – 5.0 mg/ml/kg) and SNP (5.0 μg/ml/kg). Histogram displays the percentage change in conductance in each artery evoked by administered drugs relative to the preceding control value for each infusion. Asterisks indicate a statistically significant difference compared with the baseline conductance value preceding a given infusion.

Figure 7

Quantification of the effects of acute administration of saline, drug vehicle, SKA-31 (0.1 – 5.0 mg/ml/kg) or SNP (5.0 μg/ml/kg) on left ventricular stroke volume and heart rate (panel A). No significant changes were noted for either stroke volume or heart rate in response to a given infusion compared with the values measured during the preceding control period. The histogram in panel B displays the percentage changes in left ventricular area (A_LVED) and stroke work (SW), relative to the baseline values measured during the control period preceding each indicated infusion.

Figure 8

Scatter plot displaying the relation between observed changes in left ventricular stroke work (SW) and mean aortic pressure (mP_AO) following infusions of saline, vehicle, SKA-31 and SNP. Percent changes in mP_AO, along with accompanying percent changes in SW, were first calculated in response to each infusion utilized in a given experiment. Data points from all 7 animals were then plotted against each other in a pair-wise fashion, as depicted by the individual symbols on the graph. The straight line through the symbols represents a linear regression fit to the pooled data points (r² value = 0.82; P < 0.001).