CARDIOVASCULAR RESPONSIVENESS TO VASOACTIVE AGENTS IN RATS WITH OBSTRUCTIVE JAUNDICE

1. Pressor responses to tyramine, β-phenylethylamine and angiotensin II were normal in urethane-anaesthetized rats 7 days after division of the common bile duct. The pressor response to noradrenaline was enhanced at the highest dose level used. 2. The hypotensive response to haemorrhage was exaggerated in bile duct divided rats. The exaggerated haemorrhagic hypotension of bile duct divided rats is unlikely to be the result of impaired vascular response to noradrenaline or angiotensin II, or of accumulation of false neurotransmitters by sympathetic nerves.     

EFFECTS OF NEUROPEPTIDE Y ON THE PRESSOR RESPONSES TO PHENYLEPHRINE AND TO ACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN ANAESTHETIZED RATS

1. The effects of neuropeptide Y (NPY) on the pressor responses to intravenous injections of phenylephrine and to reflex activation of the sympathetic nervous system by stimulation of the sciatic nerve were examined in anaesthetized rats. 2. NPY (10-20 micrograms/kg) always potentiated the pressor response to exogenous phenylephrine (by a mean of 28.1 +/- 5.0%). The effect of the same dose of NPY on the pressor response to sciatic nerve stimulation was variable (sometimes inhibition, sometimes potentiation). 3. NPY appears to act by potentiating post-synaptic alpha-adrenoceptor-mediated vasoconstrictor effects. It may also inhibit noradrenaline release by a presynaptic action. Thus the net effect of NPY on sympathetic activation in vivo may depend on the balance between these two opposing actions.     

BLOOD PRESSURE REGULATION IN BARORECEPTOR-DENERVATED RATS

1. Arterial baroreceptor denervation produces acute hypertension, but chronically denervated animals have an average arterial pressure that is similar to that of baroreceptor intact animals. 2. Although cardiopulmonary baroreceptors and renal compensations have been suggested to mediate the restoration of a normal average arterial pressure in sino-aortic denervated rats, such mechanisms are inconsistent with the available data. 3. At present the processes involved in the restoration and long-term maintenance of a normal average arterial pressure in chronic baroreceptor denervated animals are not known. An understanding of the regulation of arterial pressure that occurs in the absence of arterial baroreceptor reflexes may provide important new insights into the mechanisms underlying the long-term regulation of arterial pressure.     

INFLUENCE OF SEASON AND ANAESTHETIC ON CUTANEOUS VASCULAR PERMEABILITY RESPONSES TO HISTAMINE, SEROTONIN AND MAST CELL-RELEASING AGENTS IN RATS

The influences of season and anaesthetic on the cutaneous vascular permeability responses to histamine (2.5 X 10(-8) mol), serotonin (5HT, 2.5 X 10(-10) mol), and to the mast cell-releasing agents adenosine 5(1)-triphosphate (2.5 X 10(-7) mol), dextran (5 X 10(-5) g) and compound 48/80 (1 X 10(-7) g) were examined using an Evans blue dye leakage technique. In rats anaesthetized with urethane (1 g/kg i.p.), responses to irritants were significantly less than in rats given ether for the period of administration of irritants and allowed to recover consciousness. The response to histamine was mediated by H1-receptors since it was abolished by mepyramine but not by metiamide. The only seasonal variation observed was in responses to 5HT in urethane-anaesthetized rats, which were significantly less in winter than in summer. It was concluded that dye leakage responses to irritants are affected more by anaesthetic than by seasonal variation.     

DISEASE-INDUCED CHANGES IN α-ADRENOCEPTOR-MEDIATED CARDIAC AND VASCULAR RESPONSES IN RATS

1. The physiological relevance of cardiac and vascular α-adrenoceptors may increase in disease states in which β-adrenoceptors are altered. To test this, positive inotropic and vasoconstrictor responses to phenylephrine were measured in isolated tissues from rats with experimentally-induced hyperthyroidism, hypothyroidism and diabetes as well as in genetically spontaneous hypertensive rats (SHR). 2. In left atria, positive inotropic responses to phenylephrine were increased in hypothyroid and diabetic rats and abolished in hyperthyroid and SHR. 3. In contrast, phenylephrine produced increased positive inotropy in left ventricular papillary muscles from hyperthyroid rats, increased potency in diabetic rats and negative inotropic responses in hypothyroid rats. 4. The potency of phenylephrine as a vasoconstrictor in thoracic aortic rings was increased in hyperthyroid and SHR and decreased in hypothyroid rats. 5. Thus, disease states which alter β-adrenoceptor responsiveness can independently regulate atrial, ventricular and vascular responses to the α₁-adrenoceptor agonist, phenylephrine. Therefore, these disease states may alter the physiological control of the cardiovascular system by noradrenaline and adrenaline as well as the responsiveness in disease states to therapeutic agents acting via α-adrenoceptors.     

Mechanisms of sympathetic activation in heart failure

1. Heart Failure (HF) is a serious, debilitating condition with poor survival rates and an increasing level of prevalence. A characteristic of HF is a compensatory neurohumoral activation that increases with the severity of the condition. 2. The increase in sympathetic activity may be beneficial initially, providing inotropic support to the heart and peripheral vasoconstriction, but in the longer term it promotes disease progression and worsens prognosis. This is particularly true for the increase in cardiac sympathetic nerve activity, as shown by the strong inverse correlation between cardiac noradrenaline spillover and prognosis and by the beneficial effect of beta-adrenoceptor antagonists. 3. Possible causes for the raised level of sympathetic activity in HF include altered neural reflexes, such as those from baroreceptors and chemoreceptors, raised levels of hormones, such as angiotensin II, acting on circumventricular organs, and changes in central mechanisms that may amplify the responses to these inputs. 4. The control of sympathetic activity to different organs is regionally heterogeneous, as demonstrated by a lack of concordance in burst patterns, different responses to reflexes, opposite responses of cardiac and renal sympathetic nerves to central angiotensin and organ-specific increases in sympathetic activity in HF. These observations indicate that, in HF, it is essential to study the factors causing sympathetic activation in individual outflows, in particular those that powerfully, and perhaps preferentially, increase cardiac sympathetic nerve activity.     

LACK OF SYMPATHETIC AUGMENTATION IN RESPONSE TO INTRAVENOUS LOAD OF GLUCOSE IN RABBITS

1. We investigated a link between sympathetic nervous function and carbohydrate metabolism by measuring renal sympathetic nerve activity in response to intravenous load of glucose in alpha-chloralose-urethane anaesthetized rabbits. 2. Intravenous infusion of a 25% glucose solution (0.5 g/kg) over 3 min caused a transient increase in arterial blood pressure and a decrease in renal sympathetic nerve activity. Thereafter, these parameters were restored and remained around preload levels while plasma glucose and insulin concentrations were still elevated. 3. Equimolar mannitol solution produced similar patterns of change in blood pressure and nerve activity without an elevation of plasma glucose and insulin levels. 4. The transient changes in blood pressure and renal nerve activity could be attributed to acute hypervolaemia indicated by similar changes in plasma osmolality and haematocrits in the two groups of treatment. 5. The present study did not support a close relationship between carbohydrate metabolism and the sympathetic nervous system regulating cardiovascular function.     

LONG-TERM INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY AND HYPERTENSION

1. Essential hypertensive patients have been characterized by increased sympathetic nerve activity, increased peripheral vascular tone, decreased plasma volume and normal cardiac output when compared with normotensive subjects. Bilateral renal denervation reduces the magnitude or delays the onset of the blood pressure response in numerous models of experimental hypertension regardless of the aetiology of the elevation in arterial pressure. 2. Using a servocontrolled intrarenal infusion system, we have elevated intrarenal noradrenaline concentration via intermittent renal artery infusion without decreasing renal blood flow as a method of simulating selective elevation of renal sympathetic outflow. 3. Chronic intrarenal adrenergic stimulation increased arterial pressure within 24 h and this hypertension persisted for 28 consecutive days. The elevated arterial pressure was not associated with sustained increases in plasma renin activity, aldosterone, circulating catecholamines, arginine vasopressin or significant renal vasoconstriction. Urinary sodium excretion was chronically elevated and the dogs remained in negative sodium balance for the duration of the intrarenal noradrenaline infusion. 4. After 2 weeks of elevated intrarenal neurotransmitter coupled with hypertension, renal vascular reactivity to further adrenergic stimulation was significantly increased because the hypertension was maintained during continual reductions in the daily dosage of neurotransmitter allowed to be infused by the servocontroller. After only 28 days of noradrenaline infusion, renal vascular hypertrophy developed in vessels from 150–300 μm. 5. We conclude that selective and intermittent increases in intrarenal adrenergic neurotransmitter are sufficient to elicit chronic hypertension in the absence of volume expansion. This intrarenal neuroadrenergic hypertension is closely associated with the haemodynamic parameters which characterize a major subset of human essential hypertensives.     

EFFECT OF DIETARY SALT LOADING AND HIGH-CALCIUM DIET ON VASCULAR SMOOTH MUSCLE RESPONSES AND ENDOTHELIUM FUNCTION IN RATS

1. The present study examined the effects of concurrent manipulation of dietary calcium and salt on contractile responses of vascular smooth muscle (VSM) and endothelial function of aortic rings from Sprague-Dawley rats. 2. Salt loading enhanced the contractile response of the aortic rings to noradrenaline (NA), an effect that was blunted by a high calciu. intake. 3. Removal of the endothelium and incubation of aortic rings in physiological salt solution containing methylene blue increased the sensitivity of the rings t. NA. 4. The increase in the sensitivity of aortic rings induced by endothelium removal was more pronounced in aortic rings from salt-loade. rats. 5. Acetylcholine caused similar degrees of relaxation in all experimental groups, but the relaxation to histamine was smalle. (P < 0.05) in salt-loaded rats than in other groups of rats; however, after removal of the endothelium, the contractile response to histamine was higher in salt-loaded rats. 6. The results indicate that the hypersensitivity of isolated aortic rings to agonists, as observed in salt-loaded rats, is due to altered responses of the VSM and not as a result of changes in the endothelium. In addition, salt loading tends to increase the synthesis of endothelium-dependent relaxing factor. The ability of salt loading to enhance the contractile responses of VSM to agonists can be prevented by supplementing the diet with high calcium.     

EFFECT OF DIETARY SODIUM CHLORIDE ON THE DEVELOPMENT OF RENAL GLOMERULAR AND VASCULAR LESIONS IN HYPERTENSIVE RATS

• 1 The hypothesis that high levels of NaCl in the diet aggravates hypertension-associated renal vascular lesions was examined in unilaterally nephrectomized deoxycorticosterone acetate treated (DOCA) and two kidney one clip (2K1C) hypertensive rats, as well as normotensive controls.
• 2 High NaCl diet significantly increased systolic blood pressure (SBP) in DOCA rats, but had little effect on SBP in normal control rats, and did not affect the rise of SBP in 2K1C rats.
• 3 High NaCl diet was associated with a higher percentage of glomerular lesions and renal arterial and arteriolar lesions in DOCA and 2K1C rats (P<0.05).
• 4 Thus high NaCl intake exacerbated renal arterial and arteriolar and glomerular lesions in both DOCA and 2KlC hypertensive rats. In 2K1C rats this effect may be in part independent of blood pressure.

     

NORMOTENSIVE WISTAR RATS DIFFER FROM SPONTANEOUSLY HYPERTENSIVE AND RENAL HYPERTENSIVE RATS IN THEIR CARDIOVASCULAR RESPONSES TO OPIOID AGONISTS

1. The effects of three opioid receptor agonists on the blood pressure and heart rate of anaesthetized normotensive, spontaneously hypertensive and renal hypertensive rats were measured. 2. Mu agonist morphiceptin i.c.v. induced a pressor response and increase in heart rate in hypertensive rats, but hypotension in normotensive rats. After intravenous (i.v.) injection, morphiceptin produced a hypotensive response in all three groups of rats. 3. In contrast, the delta agonist DTLET i.c.v. decreased blood pressure and heart rate in hypertensive rats, but increased both pressure and beat rate in normotensive rats. After i.v. injections DTLET produced a hypertensive response and increase in heart rate in all groups of rats. 4. Kappa agonist U-50, 488H given i.c.v. induced effects similar to morphiceptin: an increase in blood pressure and heart rate in hypertensive and a decrease in normotensive rats. After i.v. injections U-50, 488H produced decreases in blood pressure and heart rate in all treated groups of rats. 5. Pretreatment with naloxone antagonized the activity of morphiceptin but prevented only the stimulating effect of DTLET in normotensive rats. Cardiovascular actions of U-50, 488H were not blocked by naloxone. 6. The results suggest that opioid agonists exert similar changes in cardiovascular function at central and peripheral sites in both models of experimental hypertension and these effects are different in normotensive rats.     

ATTENUATION OF PRESSOR RESPONSES TO SYMPATHETIC STIMULI IN THE RAT BY ENALAPRIL

Intravenous administration to pithed Wistar rats of the angiotensin converting enzyme inhibitor enalapril (0.1-1.0 mg/kg) lowered the diastolic blood pressure and reduced pressor responses occurring during electrical stimulation (1-30 Hz) of the spinal sympathetic outflow. These doses of enalapril given intravenously also attenuated pressor responses to intravenous injection of the muscarinic ganglion stimulant McNeil-A-343 (50, 100, 150 micrograms/kg) and noradrenaline (0.1-5.0 micrograms/kg). Enalapril (1.0 mg/kg, i.v.) reduced pressor responses to the nicotinic ganglion stimulant 1,1-dimethyl-4-phenyl-piperazinium (300 micrograms/kg, i.v.). These results confirmed that the actions of enalapril resemble those of captopril in the pithed rat, by causing reductions in both blood pressure and pressor responses to sympathetic stimuli.     

RENAL, ADRENAL AND VASCULAR CHANGES DURING INHIBITION OF CONVERTING ENZYME WITH CAPTOPRIL

1. In rats treated continuously with captopril (80 μg/h, i.p.), for 2 days, blood pressure decreased and adrenal angiotensin II receptor concentration was decreased from 160 fmol/mg protein (s.e.m.=9) in controls to 131 fmol/mg protein (s.e.m. = 7, P < 0.01, n= 10). However, after 5 days of continuous treatment, blood pressure had returned to normal and adrenal receptor concentrations in treated rats were not significantly different from controls (180 fmol/mg, s.e.m. = 11 and 203 fmol/mg protein s.e.m. = 14 respectively, 0.1>P>005). 2. Vascular reactivity, defined as the pressor response to exogenous angiotensin II, increased concurrently by 166 and 33% respectively. 3. In anaesthetized dogs (n= 8), captopril (1.5 mg/kg, i.v.) caused a fall in blood pressure, and urine bradykinin excretion increased from 1 08 (s.e.m.=0 14) to 1 64 μg/h (s.e.m.=0 33, P < 0 025) at 15 min. Renal blood flow increased significantly (P < 0 01) with no change in glomerular filtration rate, and there was no change in either renal venous or arterial blood bradykinin levels. 4. Thus, converting enzyme inhibition produces transient secondary changes in angiotensin receptors and vascular reactivity. Increased urine bradykinin probably reflects decreased catabolism of intrarenal bradykinin. The hypotensive effect of captopril may be due in part to raised levels of bradykinin in the kidney.     

PLASMA RENIN ACTIVITY DURING HYPOTENSIVE RESPONSES TO ELECTRICAL STIMULATION OF CAROTID SINUS NERVES IN CONSCIOUS DOGS

1. The interaction of electrical stimulation of the carotid sinus nerves (carotid sinus nerve stimulation, CSNS) with mechanisms of renin release was studied in conscious and unrestrained resting beagle dogs receiving a standardized diet (sodium intake, 4.5 mmol/kg bodyweight (bw); water intake, 91 mL/kg bw). 2. By CSNS, mean arterial blood pressure (MAP) was lowered for periods of 20 min to levels between 101 ± 4 and 56 ± 5 mmHg. 3. In another group of conscious dogs, renal perfusion pressure (RPP) was lowered to 95 ± 4 mmHg for periods of 20 min by partial suprarenal aortic occlusion in order to assess the influence of a reduced RPP on plasma renin activity (PRA) without concomitant CSNS. 4. During CSNS, PRA increased markedly (> 100%) only when MAP was reduced below 75 mmHg. 5. With aortic constriction and an RPP of 95 mmHg, the increase in PRA was 955%, which is more than three-fold higher than the increase in PRA during CSNS at MAP levels <65 mmHg (314%). 6. The observed responses indirectly support the hypothesis that basal activity in efferent renal nerve discharge is present even at rest and can be inhibited by CSNS, and furthermore suggests that CSNS attenuated the pressure-dependent renin release.     

ENDOTHELIN-1 ENHANCES VASOCONSTRICTOR RESPONSES TO SYMPATHETIC NERVE STIMULATION AND NORADRENALINE IN THE RABBIT EAR ARTERY

1. In rabbit isolated perfused ear arteries denuded of endothelium, a low concentration of endothelin-1 (0.1 nmol/L) that had no direct vasoconstrictor action produced slowly developing enhancements of vasoconstrictor responses to noradrenaline and sympathetic nerve stimulation. The enhancements reached maximal levels after 60 min of exposure to endothelin-1. 2. A higher concentration of endothelin-1 (1 nmol/L), which produced a slow-developing increase in perfusion pressure of 70 mmHg over the course of 1 h, significantly enhanced vasoconstrictor responses to sympathetic nerve stimulation for the first 30 min, after which there was no significant enhancement. Responses to noradrenaline were not enhanced by 1 nmol/L endothelin-1. 3. The enhancing effect of low concentrations of endothelin-1 on vasoconstrictor responses to sympathetic nerve stimulation and noradrenaline may play a physiological role in modulating vasomotor function.     

EFFECTS OF HOE 140 ON SYSTEMIC DEPRESSOR RESPONSES TO BRADYKININ AND MESENTERIC VASCULAR REACTIVITY IN VIVO IN PREGNANT WISTAR-KYOTO RATS

1. To examine possible changes in vascular reactivity to exogenous bradykinin (BK) and the possible role of endogenous BK in reduced mesenteric vascular reactivity in pregnant rats. The authors studied the effects of Hoe 140 on systemic depressor responses to BK and on mesenteric vascular reactivity in in situ blood-perfused mesenteric resistance vessels of 18–20 day pregnant and age-matched non-pregnant Wistar-Kyoto rats (WKY). 2. Mean intra-arterial blood pressure (MBP) of pregnant rats was lower than non-pregnant controls. Basal mesenteric perfusion pressure (BPP) was slightly, but not significantly, reduced in the pregnant group. Neither MBP nor BPP was significantly influenced by Hoe 140 (1 mg/kg. s.c.) 3. Systemic depressor responses to BK (1–30 μg/kg, i.v.) were significantly increased in pregnant rats at 1 and 3 μg/kg. Hoe 140 completely abolished systemic depressor responses to BK in either pregnant or non-pregnant animals. 4. Mesenteric vascular responses to regional administration of noradrenaline, electrical stimulation of sympathetic nerve and angiotensin II were overall decreased in pregnant compared with non-pregnant groups, but those responses were not significantly affected by Hoe 140 in either groups. 5. The results suggested that although systemic depressor responses to exogenous BK were increased, endogenous BK does not contribute to decreased mesenteric vascular reactivity in vivo in pregnant WKY.