Helma van Essen

Serotonin-mediated cardiovascular responses to electrical stimulation of the raphe nuclei in the rat

Abstract The dorsal and median raphe nuclei in rats were electrically stimulated and blood pressure and heart rate were recorded. Stimulation of each raphe nucleus caused an increase in blood pressure without affecting heart rate. The size of the increase in blood pressure depended upon the stimulus-intensity. Significant increases were already obtained with 5 sec. trains of 0.3 msec., 200 μA stimuli given at a frequency of 50 Hz. The increases in blood pressure could be obtained with electrodes within the raphe nuclei. Pretreating rats with para-chlorophenylalanine (pCPA, 100 mg/kg.day for 3 days) significantly diminished the increases in blood pressure obtained during electrical stimulation of the median raphe nucleus. However, similar pretreatment did not affect blood pressure rises induced by dorsal raphe stimulation. These data are discussed in relation to the role of central serotoninergic mechanisms in cardiovascular control.

Angiogenic potential of malignant and non-malignant human breast tissues in an in vivo angiogenesis model.

Tumors need to acquire an angiogenic phenotype for outgrowth and metastasis formation. Limited information on the angiogenic potential of specific tissues, especially human breast tissues is available. Here we describe an in vivo model, using the dorsal skin fold chamber in immunodeficient nude mice, where various tissues of human breast origin were xenografted and evaluated for their angiogenesis‐inducing potential. We found that angiogenesis was abundantly induced by all breast carcinoma tissue samples. Similar angiogenesis was induced by tissue samples from breasts with hyperplasia and apocrine metaplasia. Histologically normal tissues adjacent to the tumor induced angiogenesis in 66% of the cases. Angiogenesis was not induced by control tissues from normal healthy breasts, obtained after cosmetic breast reduction. Angiogenesis induction parallelled VEGF production by the tumor cells. The tissue induced neovascularization, found both around and in the human tissue, was functional since a tail vein injection of albumin‐FITC revealed positive tumor microcirculation within 5 min, while the tumor tissue still consisted of vital human epithelial cells after 14 days. Int. J. Cancer 77:455–459, 1998.

Determination of aortic elastic modulus by pulse wave velocity and wall tracking in a rat model of aortic stiffness

Several methods have been used to evaluate the elastic modulus of the aortic wall in the rat, but these have never been compared when used simultaneously. We measured thoracoabdominal pulse wave velocity (PWV) and changes in thoracic aorta diameter during the cardiac cycle (with wall echo-tracking) in pentobarbital-anesthetized adult male Wistar rats; half of the group had previously received vitamin D3 plus nicotine (VDN) in order to increase the stiffness of the aortic wall. The Moens-Korteweg elastic modulus (EMK) was calculated from PWV and the ratio of the internal diameter to the medial thickness determined by histomorphometry following in situ pressurized fixation. The incremental elastic modulus (Einc) was calculated from the distensibility coefficient and end-diastolic diameter measured by wall echo-tracking and the medial thickness determined by histomorphometry. Both values were higher in VDN rats than in controls: Einc 8.9 ± 0.5 and 5.7 ± 0.4·106 dyne/cm2, p < 0.05; EMK 7.6 ± 0.5 and 4.1 ± 0.5·106 dyne/cm2, p < 0.05. Einc was greater than EMK and this was partially due to the fact that the in vivo end-diastolic diameter measured by ultrasound was greater than the mean aortic diameter measured ex vivo by histomorphometry. In conclusion, different methods for the measurement of the elastic properties of the aortic wall gave similar results in controls and in a rat model of aortic stiffness.

Disproportional Arterial Hypertrophy in Hypertensive mRen-2 Transgenic Rats

In the present study, we investigated the role of enhanced vascular renin-angiotensin activity in vascular hypertrophy. We used transgenic (mRen-2)27 (renin TGR) rats, spontaneously hypertensive rats (SHR), and their respective normotensive control rats to study in situ pressure-diameter relationships in second-generation mesenteric arterial branches (in vivo diameter, 400 to 500 microns) over a pressure range of 0 to 200 mm Hg. We studied pressure-diameter curves under both control (Tyrodes solution) and fully relaxed (Tyrodes solution containing 100 mg/L potassium cyanide) conditions. From these curves, we determined mechanical properties at operating blood pressure. In both hypertensive strains, mesenteric arterial media cross-sectional area was increased, with a significantly (P < .05) stronger degree of hypertrophy in renin TGR rats. Arterial distensibility of relaxed vessels was decreased to an equal degree in both hypertensive strains. Under control conditions, distensibility was higher in SHR than in renin TGR rats but still significantly reduced compared with distensibility in normotensive rats. Wall tension was increased to an equal degree in both hypertensive strains, whereas circumferential wall stress was normal in SHR but significantly (P < .05) reduced in renin TGR rats. These results indicate that whereas vascular hypertrophy in SHR causes adaptive normalization of arterial wall stress, enhanced vascular renin-angiotensin activity causes vascular hypertrophy in excess of the hypertrophy associated with pressure elevation alone.

Microvascular actions of calcium channel antagonists

The microvascular actions of three calcium channel antagonists were studied in intact spontaneously hypertensive rats (SHR) provided with a dorsal striated muscle microcirculatory chamber. Verapamil and the dihydropyridine derivatives nifedipine and felodipine reduced mean arterial blood pressure (MAP) in a dose-dependent manner. They dilated arterioles of different sizes, with the most pronounced effect being on the smallest precapillary arterioles. Venular diameters were not affected by the calcium antagonists. Approximately 60% of the small arterioles showed a rhythmic pattern of vasodilatation and constriction. This pattern of spontaneous vasomotion was completely blocked by the calcium channel antagonists, especially those of the dihydropyridine type. It is concluded that (a) small precapillary arterioles play an important role in the vasodilator action of calcium channel antagonists, and (b) arteriolar vasomotion depends on vascular smooth muscle cell calcium influx.

Renal inflammatory markers during the onset of hypertension in spontaneously hypertensive rats.

Early blockade of the renin–angiotensin system is successful in delaying the development of hypertension in spontaneously hypertensive rats (SHRs) and ameliorating organ damage by inhibition of the inflammatory response. In this study, we investigated the role of the angiotensin II type 1 receptor (AT1R) in the early renal inflammatory response in SHR. Blood pressure development and renal inflammatory markers were measured in 4-, 8- and 12-week-old SHR and age-matched Wistar Kyoto (WKY) rats. Separate groups of SHRs were transiently treated with the AT1R blocker losartan between 4 and 8 weeks of age. Urinary excretion of the renal injury markers osteopontin and neutrophil gelatinase-associated lipocalin increased in young SHR. Further, renal expression of inflammatory genes was also increased in young SHR. Losartan inhibited the increase of these inflammatory markers. In contrast, gene expression of the renal injury marker and T-cell inducer kidney injury molecule-1 (KIM-1) was reduced in 4-week-old SHR when compared with WKY. Similarly, the T-cell marker CD3 was significantly decreased in 4-week-old SHR. These effects were not antagonized by AT1R blockade. This study confirms the presence of an early renal inflammatory response in SHR that can be blocked by AT1R antagonism. In addition, it demonstrates that KIM-1 does not behave as a pure kidney injury marker in young SHR, but may reflect kidney maturation.

Systemic and regional hemodynamic actions of calcium entry blockers in conscious spontaneously hypertensive rats

In the present study we investigated systemic and regional hemodynamic effects of the calcium entry blockers nifedipine, verapamil and PY 108-068 in conscious SHR. For systemic hemodynamic studies the animals were instrumented with an electromagnetic flowprobe on the ascending aorta, whereas for regional hemodynamic studies miniaturized Doppler flowprobes were implanted on the superior mesenteric and left renal artery and on the abdominal aorta. All three drugs caused a dose-dependent fall in mean arterial pressure and total peripheral resistance. Nifedipine and PY 108-068 increased cardiac output and heart rate, whereas verapamil only did so at high doses. Administration of each calcium entry blocker caused a dose-dependent fall in skeletal muscle vascular resistance, with renal and mesenteric resistance remaining virtually unchanged. A similar effect was observed after the administration of nifedipine to normotensive WKY rats. Surgical elimination of sino-aortic baroreflexes caused a 10 fold increase in antihypertensive potency of the three drugs in SHR. Moreover, dilatation in these animals was uniform in all beds studied. The results indicate that the three calcium entry blockers used are essentially non-selective vasodilators but that baroreflex mechanisms prevent vasodilatation in the renal and mesenteric beds in intact animals.

Hemodynamic effects of the arteriolar vasodilators hydralazine, dihydralazine and endralazine in the conscious spontaneously hypertensive rat

The hemodynamic effects of the vasodilators hydralazine, dihydralazine and endralazine were studied in conscious, unrestrained spontaneously hypertensive rats (SHR) equipped for chronic hemodynamic measurements. The arteriolar vasodilators hydralazine (0.3 mg/kg i.a.) and dihydralazine (0.3 mg/kg i.a.) caused a rapid fall in blood pressure and peripheral resistance, lasting up to 24 h in the case of dihydralazine. Immediately after injection, the cardiac output and heart rate were increased significantly. These effects only lasted for 1-2 h. The hemodynamic pattern of the new vasodilator endralazine (0.1-1 mg/kg i.a.) was very similar, with a duration of action similar to that of dihydralazine. The role of baroreceptor reflexes in the early hemodynamic effects of vasodilators was studied by comparing the effects of 0.3 mg/kg hydralazine in baroreflex-denervated and non-denervated SHR. The decrease in blood pressure and peripheral resistance was significantly larger in the denervated SHR, whereas increases in cardiac output and heart rate were almost completely absent in these animals. These data suggest that baroreceptor reflexes oppose the early fall in blood pressure and peripheral resistance induced by vasodilators. However, the activity of the baroreflex seems of very short duration, suggesting a rapid adaptation to the prevailing blood pressure. Moreover, the data show that endralazine is an effective arteriolar vasodilator in conscious SHR.

Preferential small arteriolar vasodilation by the potassium channel opener, BRL 38227, in conscious spontaneously hypertensive rats

The microvascular effects of the potassium channel opener, BRL 38227 (the active enantiomer of cromakalim), were investigated in conscious spontaneously hypertensive rats (SHR) provided with a chronic dorsal microcirculatory chamber. BRL 38227 decreased blood pressure and increased heart rate in a dose-dependent manner. It dilated arterioles of different sizes, with the most pronounced effect on the smallest precapillary arterioles. Venule diameters were not significantly affected by BRL 38227. The data show a preferential sensitivity of small precapillary arterioles for potassium channel opening.

Lack of renal vasodilation during intrarenal infusion of synthetic atriopeptin II in conscious intact SHR.

Synthetic atriopeptin II (APII) was infused directly into the right renal artery of intact conscious SHR at rates of 0.25-1 microgram/kg/min, while simultaneously measuring blood pressure (MAP) and selected regional blood flows. The latter were measured using chronically implanted miniaturized Doppler flowprobes that were placed on the right and left renal artery, superior mesenteric artery and abdominal aorta. The effects of intrarenally (i.r.) infused APII on these vascular beds were compared to the effects of the same amounts of APII given intravenously (i.v.) in the same SHR. I.r. and i.v. infusions caused similar reductions of MAP and all four blood flows. Also effects on calculated resistances were comparable, implying that resistance increased most in the mesentery and least in the two kidneys. The increase in right renal resistance during i.v. infusions of APII was not different from the effect during i.r. infusions. Also, during i.r. infusions into the right kidney, effects on the left and right kidney were not different. Our observations suggest that synthetic APII has no direct effects on the renal vasculature of intact conscious SHR.