The horse-human dyad: can we align horse training and handling activities with the equid social ethogram?

This article examines the recently completed equid ethogram and shows how analogues of social interactions between horses may occur in various human-horse interactions. It discusses how some specific horse-horse interactions have a corresponding horse-human interaction - some of which may be directly beneficial for the horse while others may be unusual or even abnormal. It also shows how correspondent behaviours sometimes become inappropriate because of their duration, consistency or context. One analogue is unlikely to hold true for all horse-human contexts, so when applying any model from horse-horse interactions to human-horse interactions, the limitations of the model may eclipse the intended outcome of the intervention. These limitations are especially likely when the horse is being ridden. Such analyses may help to determine the validity of extrapolating intra-specific interactions to the inter-specific setting, as is advocated by some popular horse-training methods, and highlight the subsequent limitations where humans play the role of the 'alpha mare' or leader in horse handling and training. This examination provides a constructive framework for further informed debate and empirical investigation of the critical features of successful intra-specific interactions.

Vascular hypertrophy in renal hypertensive spontaneously hypertensive rats.

Vascular smooth muscle cells isolated from spontaneously hypertensive rats (SHR) replicate faster in vitro than do cells from Wistar-Kyoto (WKY) rats, suggesting that the vascular hypertrophy seen early in the life of SHR might be at least partially caused by abnormal cellular growth properties in vivo. To test whether specific growth stimuli produce more extensive hypertrophy in SHR than WKY rats, we compared their cardiovascular growth responses to two-kidney, one clip renal hypertension. Six-week-old animals were subjected to either renal artery clipping or sham operation. Four weeks after renal artery clipping, there was a proportionately smaller rise in systolic blood pressure in SHR than WKY rats (21% and 44%, respectively); however, the overall level of systolic blood pressure achieved in the two rat strains differed by less than 10 mm Hg (4%). Limitations in the blood pressure responses of SHR to renal artery clipping were not due to inadequate development of left ventricular hypertrophy, as this was greater in SHR than WKY rats; however, aortic hypertrophy was similar in both strains. Aortic DNA content changes in SHR were consistent with a significant hyperplasia of medial smooth muscle cells, whereas in WKY rats, there was cellular hypertrophy. Small and medium-sized arteries of the mesenteric vasculature were also hypertrophied in SHR, and the medial cross-sectional area increased by 63% and 114%, respectively, compared with increases of only 15% and 23% in WKY rats. Strain differences between the sham-operated rat groups were small.(ABSTRACT TRUNCATED AT 250 WORDS)

Sympathoadrenal system is critical for structural changes in genetic hypertension.

In spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, we examined tissue and adrenal norepinephrine concentrations, left ventricular (LV) weight, LV weight/body weight ratio (LV/BW), hindquarter resistance properties, ie, perfusion pressures at maximum dilatation and constriction (PPmax, PPmin), and the slope of the methoxamine log dose-PP curve. In series 1, we studied 4-week-old controls (SHRc, WKYc), sympathectomized rats (SX; SHRsx, WKYsx), and SX rats also given prazosin (SXP; SHRsxp, WKYsxp). With SX and SXP, adrenal norepinephrine concentrations increased in both strains, but tissue (LV, muscle, kidney) norepinephrine was depleted. At 4 weeks, LV/BW, PPmin, and PPmax were all greater in SHRc than in WKYc. With SX, these differences between strains remained unchanged, but SXP abolished them completely, indicating the importance of blockade of alpha-adrenergic receptor stimuli of adrenal origin. In SHRc (but not in WKYc), there was evidence of reinnervation after 4 weeks of SX. Hence, in series 2, the SXP period was extended to 8 weeks, and we studied SHRc, WKYc, SHRsxp, and WKYsxp. Systolic blood pressure was already elevated at 4 weeks in SHRc, and by 35 weeks it was 64 mm Hg greater than in WKYc. At 21 and 35 weeks, LV/BW, PPmax, PPmin, and slopes were all greater in SHRc than in WKYc, and the findings suggested greater LV and vascular hypertrophy than at 4 weeks. In SHRsxp hypertension, LV hypertrophy and the vascular changes were completely prevented over the entire 35-week observation period. SXP mainly affected SHR and had few effects on WKY rats. The sympathetic nerves and adrenals are probably the sources of alpha-adrenergic receptor stimulation in young SHR. They account for the development of hypertension and for most of the cardiovascular structural differences between SHR and WKY rats.

Chronic angiotensin II type 1 receptor antagonism in genetic hypertension: effects on vascular structure and reactivity.

OBJECTIVE AND DESIGN: The aim of the study was to assess the role of angiotensin II (Ang II) in the maintenance of cardiovascular hypertrophy and the abnormal vascular amplifier properties in spontaneously hypertensive rats (SHR) with established hypertension. Losartan, a type 1 Ang II receptor antagonist, was administered to SHR and Wistar-Kyoto (WKY) rats, and its effects on blood pressure, cardiac hypertrophy, vascular morphology and hindquarter vascular amplifier properties assessed at the end of treatment and 3 months later. METHODS: Losartan was administered for 6 weeks to 14-week-old SHR (60 mg/kg per day orally). A bio-equivalent dose (20 mg/kg per day orally) was administered to age-matched WKY rats. Systolic blood pressure (SBP) was measured in conscious rats by tail-cuff plethysmography. Morphological changes were assessed both in the heart, from the ratio of the weight of the left ventricular wall plus septum to body weight, and in blood vessels from the medial cross-sectional areas of the abdominal aorta and mesenteric arteries. Vascular amplifier properties were measured by perfusion of the rat hindquarters under conditions of full dilation (papaverine hydrochloride) and incremental constriction with methoxamine hydrochloride. RESULTS: Losartan lowered SBP in SHR to normotensive WKY rat levels during treatment. Left ventricular hypertrophy and aortic cross-sectional area were reduced at the end of treatment to WKY rat levels; mesenteric artery cross-sectional area was reduced to a lesser extent. The abnormal hindquarter vascular amplifier properties of the SHR were normalized by losartan. Three months after treatment ended, SBP had returned to untreated SHR levels. Left ventricular hypertrophy and the abnormal hindquarter vascular amplifier properties had also partially redeveloped. CONCLUSIONS: Our findings support the hypothesis that Ang II contributes to the maintenance of cardiovascular hypertrophy and the abnormal vascular amplifier properties in SHR with established hypertension. However, its role appears to be variable and to depend on the type of vascular bed. Other, pressure-independent, factors may also contribute to vascular hypertrophy.

Long-term angiotensin II antagonism in spontaneously hypertensive rats: effects on blood pressure and cardiovascular amplifiers.

1. The angiotensin II type 1 receptor antagonist, losartan, prevented the development of hypertension in spontaneously hypertensive rats (SHR). 2. Losartan also prevented the development of left ventricular hypertrophy and vascular amplifier abnormalities. 3. Part of the hypotensive effect induced by long-term treatment with losartan persisted for a long time after the withdrawal of treatment. 4. The results support the hypothesis that angiotensin II contributes to the development of hypertension and cardiovascular hypertrophy in SHR.

Relationships between the cardiovascular effects of alpha-methyldopa and its metabolism in pontomedullary noradrenergic neurons of the rabbit.

We compared the biotransformation of equipotent intracisternal (i.c., 600 micrograms/kg) and intravenous (i.v., 50 mg/kg) doses of alpha-methyldopa (alpha-MD) to alpha-methylnorepinephrine (alpha-MeNE) in the five major (A1, A2, A5, A6, and A7) noradrenergic nuclei of the rabbit brain, in relation to their cardiovascular effects. Peak effects on blood pressure and heart rate occurred 2-3 h after administration and persisted for 8 h. Three hours after i.v. alpha-MD, norepinephrine (NE) content throughout the five cell group regions was greatly reduced. However, total catecholamine (CA) content (NE plus alpha-MeNE) in the five cell groups increased by up to 300% due to accumulated alpha-MeNE. Eight hours after the i.v. dose, CA content throughout all five cell groups remained elevated. Following i.c. alpha-MD, a similar pattern of effect was observed in the A1, A2, and A5 regions. In the A6 and A7 regions, the effects were small and transient. Three hours after the i.c. dose, there was some biotransformation of alpha-MD but CA content was not affected. By 8 h, alpha-MeNE accounted for only a small fraction of the CA content. These results suggest that A1, A2, and A5 areas could be contributing to alpha-MD's cardiovascular effects. The elevation in CA content may be responsible for the activation of noradrenergic depressor pathways and blood pressure reduction.

Effect of autonomic blockade on the hemodynamic responses of normal human subjects to acute intravenous milrinone.

We studied the hemodynamic effects of four doses of milrinone, administered by intravenous (i.v.) infusion alone and after autonomic blockade with prazosin, propranolol, atropine, and clonidine. Plasma concentrations of milrinone (50-600 ng/ml) were similar to those used for the treatment of cardiac failure and were unaltered by autonomic blockade. When given alone, milrinone induced dose-dependent increases in heart rate (maximum increase 21 +/- 4, SEM, beats/min) and cardiac output (CO) (maximum 44 +/- 9%) and reduced systemic vascular resistance (SVR) by a maximum of 32 +/- 5%. After autonomic blockade, milrinone caused a similar fall in SVR and a smaller but significant (7 +/- 2 beats/min) rise in heart rate, but no change in CO. The increase in CO produced in normal humans by acute i.v. infusions of milrinone depends on intact cardiovascular reflexes.

High-performance liquid chromatographic analysis of norepinephrine and alpha-methylnorepinephrine in microdissected noradrenergic cell groups of the rabbit brain.

A high-performance liquid chromatographic method with electrochemical detection has been developed to measure norepinephrine (NE) and alpha-methylnorepinephrine (alpha-MeNE) in microdissected noradrenergic cell groups of the rabbit brain stem. The method is shown to be specific, accurate and precise and has a sensitivity of 0.5 pmol per sample. The method has been applied to the measurement of NE and alpha-MeNE levels in the A1, A2, A5, A6 and A7 noradrenergic cell groups after administration of the antihypertensive drug alpha-methyldopa (alpha-MD), so that the sites of action of alpha-MD within the central nervous system may be localised.

Development and application of a superfusion technique for the study of renin secretion in rat renal cortical cells.

A dynamic column superfusion system has been developed for the study of renin secretion in rat renal cortical cells. Cells were isolated by collagenase digestion and mechanical dispersion, before suspension with polyacrylamide beads and superfusion with oxygenated physiological medium. Renin was detected in the superfusate by incubation of fractions with excess nephrectomized sheep substrate in the presence of angiotensinase inhibitors followed by radioimmunoassay of the angiotensin I generated. Optimized methodology included a purpose-built polytetrafluorethylene flow cell, a 1 h equilibration to achieve a steady state, 5 min eluate collections, a 15 min stimulatory and a 30 min recovery period, and duration of perfusion of up to 270 min. Significant increments above baseline renin release were seen with the stimuli of adrenaline, noradrenaline and isoprenaline. These could be demonstrated with concentrations of 10(-9) mol/l (adrenaline), 5 X 10(-10) mol/l (noradrenaline) and 10(-9) mol/l (isoprenaline). This technique has significant advantages over previous methods for the study of renin secretion in vitro at the cellular level. It is reproducible and sensitive, and avoids many of the limitations of static cell suspension and kidney slice methods.

Evidence for a predominantly central hypotensive effect of alpha-methyldopa in humans.

We examined the time course and extent to which central and peripheral mechanisms contribute to the short-term effects of a 500-mg oral dose of alpha-methyldopa on supine mean arterial pressure, cardiac output, and total peripheral resistance, as well as its effects on total urinary excretion of norepinephrine and its metabolites, in five subjects with essential hypertension. Total peripheral resistance was reduced significantly 1 hour after alpha-methyldopa administration and remained so for the ensuing 7 hours of the study (p less than 0.05). A small but significant reduction in mean arterial pressure occurred 7 hours after the dose (p less than 0.05), while cardiac output did not change significantly. Total 24-hour urinary norepinephrine and metabolite excretion was reduced by 8.1 mumol (35% compared with placebo). The relative distribution of urinary norepinephrine metabolites was unaffected by alpha-methyldopa, and the catecholamine metabolites of alpha-methyldopa, alpha-methylnorepinephrine and alpha-methylnormetanephrine did not account for this reduction. Competitive inhibition of methyldopa transport across the blood-brain barrier and into the central nervous system by large oral doses of isoleucine antagonized most of the effect of alpha-methyldopa. The effects on total peripheral resistance were completely abolished, and small, insignificant changes during the 7-hour study were similar to those observed after placebo. Changes in mean arterial pressure were not significant; however, 24-hour total urinary norepinephrine and metabolite excretion increased by 6.1 mumol to 22.7 mumol (24.7 mumol excreted after placebo). Adding benserazide to the alpha/methyldopa-isoleucine dose regimen in an attempt to inhibit any residual, presumably peripheral, effects of alpha-methyldopa caused little, if any, further antagonism.(ABSTRACT TRUNCATED AT 250 WORDS)

Contribution of central and peripheral mechanisms to the antihypertensive effects of alpha-methyldopa in the rabbit.

We compared the effects of one intracisternal (0.6 mg/kg i.c.) and two intravenous (25 and 50 mg/kg i.v.) doses of alpha-methyldopa (alpha-MD) on blood pressure, heart rate, and plasma catecholamines in rabbits before and 2-3 weeks after intracisternal administration of 6-hydroxydopamine (6-OHDA). Intracisternally administered alpha-MD lowered heart rate, blood pressure, and plasma noradrenaline levels. Peak effects on heart rate and blood pressure were observed 2-3 h after administration. Three hours after intracisternally administered alpha-MD, plasma noradrenaline levels were reduced by 58%. Two to three weeks after 6-OHDA administration, the central mechanism responsible for the falls in heart rate, blood pressure, and plasma noradrenaline levels was abolished. The effects of intravenously administered alpha-MD (50 mg/kg) on heart rate, blood pressure, and plasma noradrenaline levels were attenuated but not completely abolished by destruction of central catecholaminergic neurons with 6-OHDA. These residual effects of alpha-MD most probably represent the peripheral effects of alpha-methylnoradrenaline at sympathetic terminals. The relative magnitudes of central to peripheral effects of alpha-MD on heart rate and blood pressure are dose dependent. After the lower intravenous dose (25 mg/kg), which achieves plasma alpha-MD concentrations similar to those found in humans, central mechanisms predominant. At higher doses, central and peripheral mechanisms contribute equally to these effects.

Factors in the control of plasma renin activity and concentration in Type 1 (insulin-dependent) diabetes.

Possible factors involved in the control of plasma renin activity (PRA) and concentration (PRC) have been analysed in 49 patients with long-standing Type 1 diabetes and in 40 healthy controls matched for age and sex. Eighteen of the diabetic subjects were clinically free of all microvascular and macrovascular complications of their disease (Group A); 31 had proliferative retinopathy (Group B). Both lying and standing PRA and PRC were similar in Group A and healthy controls. Mean PRA was 50-115% higher in Group B diabetics than in controls (P less than 0.001 supine and erect) and 50-70% higher than in Group A diabetics (P less than 0.05 supine and erect); PRC also was 60% higher in Group B than in Group A (P less than 0.05 supine and erect). Control subjects showed significant falls in both PRA and PRC with increasing age, while Groups A and B showed significant falls in PRA or PRC with age. Group A showed a significant inverse correlation between systolic blood pressure and supine PRC (r = -0.57), but this was not significant in the controls and was completely absent in Group B. With correction for the effect of age there were significant relationships of PRA and PRC with sodium excretion in the controls and in Group A, but not in Group B. PRA and PRC are thus normal in uncomplicated long-standing Type 1 diabetes, but regulation of renin secretion appears to be impaired in patients with microvascular disease. Renin secretion inappropriate to their blood pressure and sodium status may contribute to maintenance of their relative hypertension.

Cardioselectivity, kinetics, hemodynamics, and metabolic effects of xamoterol.

Xamoterol is a new orally active partial beta-adrenoceptor agonist. Its kinetics, hemodynamic and metabolic effects, and cardioselectivity were investigated in eight normal subjects. Plasma xamoterol concentrations after 100 micrograms/kg iv declined biexponentially over 8 hr and t 1/2 beta averaged 2.6 hr. Resting heart rate (HR) increased slightly in the supine position but was unchanged on sitting. Systolic blood pressure (SBP) rose by 5 to 10 mm Hg and cardiac index (CI) rose 15% to 20%. Both parameters were above control values 6 hr after dosing, when plasma xamoterol concentrations had fallen to about 10 ng/ml. There were no changes in diastolic or mean arterial pressure (MAP). During graded exercise the effects of xamoterol on HR and SBP were the reverse of those at rest, with lowering of exercise HR and SBP at higher work loads. CI during exercise was not altered by xamoterol. Doses of xamoterol were calculated from the kinetic data to give plasma concentrations of 100, 200, 400, and 800 ng/ml. HR and blood pressure effects at each xamoterol level were compared before and after inhibition of cardiovascular reflexes with prazosin, atropine, and clonidine. Hemodynamic effects of xamoterol and isoproterenol were compared. Before autonomic block xamoterol increased HR by 10 bpm and MAP by 7 mm Hg at the highest dose. After autonomic block there was a 200% to 300% rise in HR at each dose and MAP still rose. The rise in MAP after block could be entirely accounted for by a 23% increase in CI because total peripheral resistance did not change. The effects of isoproterenol after autonomic block were a rise in HR and a fall in MAP. Metabolic responses to xamoterol were measured at the four dose levels. There was a dose-related increase in nonesterified fatty acids and a fall in plasma lactate levels but no changes in plasma renin activity or blood glucose. Results suggest that xamoterol is a cardioselective partial beta-adrenoceptor agonist in man.

Cardioselectivity of prenalterol and isoproterenol.

We examined the hemodynamic effects and kinetics of prenalterol, a new beta-adrenoceptor agonist, in 10 normal subjects. There is some doubt whether prenalterol is selective for beta 1 adrenoceptors in animals; therefore, we also compared its cardioselectivity with that of the nonselective agonist, isoproterenol, with respect to heart rate (HR) and blood pressure (BP) responses after inhibition of cardiovascular reflexes with atropine, clonidine, and phentolamine. After intravenous (2.5 mg) and oral (10 mg and 100 mg) dosing, t 1/2 beta was 2 to 3 hr. Oral bioavailability averaged 33% and was independent of dose. Oral prenalterol, 10 mg and 100 mg, increased resting HR, systolic BP, and cardiac index by up to 27% but had no significant effects during graded exercise. Prenalterol infusions were calculated to attain steady-state plasma concentrations of 10, 20, and 40 ng/ml. HR and BP effects of the levels (10.8, 23.6, and 47.4 ng/ml) were compared with those of 0.5, 1.5, and 2.5 micrograms isoproterenol. Before autonomic block, prenalterol increased HR by 10 bpm at the highest dose and mean arterial pressure (MAP) by 10 mm Hg. In contrast, HR rose and MAP fell after isoproterenol. After block, at the highest doses of prenalterol and isoproterenol, there was an average rise in HR of 42 and 27 bpm; BP was almost maintained after the former but fell by 33 mm Hg after the latter. Prenalterol is an inotropic drug that has the effects of a full cardioselective beta-adrenoceptor agonist. Its inotropic effects are evident at doses that have little effect on HR because of the modifying effect of cardiovascular reflexes. The hemodynamic effects are most obvious at rest when sympathetic tone is low.

Increased plasma renin activity in type 1 diabetes with microvascular disease.

Plasma renin activity was measured in thirty-one subjects with Type 1 diabetes and proliferative retinopathy, and in seventeen matched diabetic subjects without evidence of any complications of their disease. The two groups were comparable for age, sex, smoking habits and duration of diabetes. Systolic and diastolic blood pressures were significantly higher in the patients with retinopathy (P less than 0.025 and P-0.05 respectively) and HbA1 was greater (P less tha 0.005) than in the patients without complications. Plasma renin activity, both lying and standing, was higher in the patients with retinopathy than in the uncomplicated group (P less than 0.05 for each). There were no correlations between plasma renin activity and mean blood pressure, HbA1 or fasting blood glucose. These findings raise the possibility that the renin-angiotensin system might be implicated in the pathogenesis of diabetic microvascular.