Effect of parathyroid hormone on myocardial bloodflow and infarct size following coronary artery occlusion in the dog.

OBJECTIVE: To investigate the cardioprotective effect of both the amino terminal of bovine parathyroid hormone (bPTH-[1-34]) and human parathyroid hormone (hPTH-[1-84]) following coronary artery occlusion. DESIGN: Animals were randomly assigned to one of three treatment groups following circumflex coronary artery occlusion. ANIMALS: Experiments were performed using 19 mongrel dogs of either sex. As four animals died during experimentation, data are shown for 15 dogs (n = 5 for each treatment group). INTERVENTIONS: Animals received saline, bPTH-(1-34) or hPTH-(1-84) following occlusion of the circumflex coronary artery. Peptides were given at 0.008 nmol/kg/min. All treatments were infused directly into the coronary circulation. Infusion rate was 1 mL/min for 10 mins at 30 min intervals until the end of the experiment (480 mins after onset of occlusion). Hemodynamic variables were monitored throughout the experiment. Radioactive microspheres were injected 10 mins before, and 30, 240 and 480 mins following, occlusion of the coronary vessel to determine regional myocardial blood-flows. At the end of the experiment, area at risk and infarct size were measured by simultaneous infusion of Evans blue dye and triphenyl tetrazolium chloride stain. MAIN RESULTS: Neither bPTH-(1-34) nor hPTH-(1-84) significantly reduced area of risk or infarct size as a percentage of area at risk compared with controls. These results were corroborated by regional blood-flows measured using radioactive microspheres. There was no significant difference in hemodynamic variables among the groups except that left atrial pressure was consistently lower following treatment with hPTH-(1-84). CONCLUSIONS: No evidence was found that either bPTH-(1-34) or hPTH-(1-84) salvaged ischemic myocardium in a canine model of myocardial infarction. Treatment with hPTH-(1-84) was associated with a reduction in left atrial pressure. This latter phenomenon may constitute a beneficial effect of this peptide on diastolic myocardial function.

Integrated cardiovascular function in the conscious streptozotocin-diabetic deoxycorticosterone-acetate-hypertensive rats.

Blood pressure, heart rate, and left ventricular function were measured in conscious diabetic Sprague-Dawley rats subjected to 5 weeks of deoxycorticosterone acetate (DOCA) treatment which was started 1 week following intravenous injection of streptozotocin (STZ) (60 mg/kg) to induce diabetes mellitus. It was found that chronic administration of DOCA in nondiabetic animals caused an increase in blood pressure and functional parameters of left ventricle, and a decrease in heart rate and plasma insulin levels. Normotensive diabetic rats exhibited hyperglycemia, hypoinsulinemia, and a lower body weight as compared with control animals but did not show significant abnormalities in cardiovascular function. DOCA-hypertensive STZ-diabetic rats had similar hyperglycemia, milder hypoinsulinemia, and a significantly lower rate of left ventricular relaxation and systolic blood pressure compared with the nondiabetic DOCA-hypertensive animals. It is concluded that the addition of DOCA hypertension to intact 6-week STZ-diabetic Sprague-Dawley rats results in the occurrence of cardiac dysfunction.

Effect of inspiratory-phase negative pressure breathing on urine flow in man.

We investigated the effect of negative pressure breathing during the inspiratory phase only (intermittent NPB) in 9 healthy male subjects who were in a sitting position and had no food or fluid intake for 12 h before the study. Intermittent NPB was without effect on urine flow and urinary sodium excretion but caused a significant increase in creatinine clearance. Plasma renin activity was significantly reduced, whereas plasma antidiuretic hormone (ADH), atrial natriuretic factor (ANF), and aldosterone levels were unaffected. To determine whether the blunted urinary response to intermittent NPB was a postural phenomenon, the study was repeated in 6 of the subjects while supine. Under these conditions there was a significant increase in urine flow and plasma ANF levels, but no change in all other measured variables. These results are consistent with a role for ANF, but not ADH, in the diuresis seen in supine subjects during NPB.

Comparative effects of Des Leu Angiotensin I and Angiotensin II on AVP secretion from the hypothalamoneurohypophysis and pituitary of the rat.

In the present study we compared the effects of Des Leu Angiotensin I (Des Leu AI) with Angiotensin II (AII) on the secretion of vasopressin (AVP) from the isolated hypothalamoneurohypophyseal system (HNS) and isolated posterior pituitary gland of the rat. Administration of 10(-6)M, 10(-5) M and 10(-4) M Des Leu AI was without significant effect on AVP secretion from the HNS. A similar phenomenon was seen in the posterior pituitary with 10(-6) M and 10(-5) M Des Leu AI, although 10(-4) M significantly increased AVP release. Administration of 10(-6) M AII was without significant effect in either preparation, although 10(-5) M and 10(-4) M AII caused significant dose-dependent increases in AVP secretion over control release that were similar in both the HNS and posterior pituitary gland. These results suggest that Des Leu AI is not a physiologically relevant stimulus of AVP secretion when restricted to this area of the rat brain. They are also consistent with the presence of receptors sensitive to AII in the pituitary gland of the rat.

Requirement for solutions with oncotic pressure to release ANF during blood volume expansion in conscious and anesthetized rats.

We examined the effect of a 30% blood volume expansion with either blood, isotonic saline, or isotonic saline plus albumin on the release of immunoreactive-atrial natriuretic factor (IR-ANF) in conscious and barbiturate-anesthetized rats. Immediately prior to volume expansion, resting plasma IR-ANF levels were significantly (p less than 0.05) higher in the conscious animals (61 +/- 5 pg/mL, n = 19) compared to the anesthetized animals (41 +/- 3 pg/mL, n = 19). Volume expansion with blood from donor rats significantly (p less than 0.05) elevated IR-ANF in both groups, but the increase in the conscious rats (+492 +/- 32 pg/mL, n = 6) was significantly (p less than 0.05) greater than that of the anesthetized rats (74 +/- 25 pg/mL, n = 6). Similarly, volume expansion with isotonic saline containing 38 mg/mL albumin significantly (p less than 0.05) elevated IR-ANF levels in both groups, but the increase in the conscious group (379 +/- 102 pg/mL, n = 7) was significantly (p less than 0.05) greater than that of the anesthetized group (94 +/- 32 pg/mL, n = 7). These elevations in IR-ANF levels were not significantly different between either of the conscious groups or either of the anesthetized groups. Volume expansion with isotonic saline alone did not have any significant effect upon resting IR-ANF levels in either conscious (+8 +/- 14 pg/mL, n = 6) or anesthetized (-7 +/- 6 pg/mL, n = 6) animals. From these results, it would appear that a) isotonic saline alone does not stimulate IR-ANF release when used to expand blood volume, and b) barbiturate anesthesia significantly lowers resting plasma IR-ANF levels and attenuates the release of IR-ANF in response to volume expansion.

Association of DOCA hypertension with induction of atherosclerosis in rats with short-term diabetes mellitus.

We investigated the effect of deoxycorticosterone acetate (DOCA)-induced hypertension on plasma lipid and cholesterol levels and the development of vascular atherosclerotic changes in male Wistar rats injected with streptozotocin (STZ) or saline (CON). Rats given STZ alone demonstrated a mild hyperlipidemia and hypercholesterolemia without any change in blood pressure. One week of DOCA administration was without effect on blood pressure in CON and STZ groups, but at 3 and 6 wk caused a significant and similar elevation in both groups. This DOCA-induced elevation in blood pressure appeared to be associated with the increase in plasma lipid and cholesterol levels seen in both CON and STZ groups at 3 and 6 wk, although the elevation in lipid and cholesterol levels was significantly more pronounced in the STZ rats. Both CON and STZ groups injected with DOCA developed significant pathological changes in all vessels under investigation. However, the degree of atherosclerosis appeared, from a semiquantitative analysis, to be worse in the thoracic aortas and renal arteries of the STZ group. Neither normotensive group developed any atherosclerosis. It is concluded that hypertension is associated with atherosclerosis in normal rats and rats with short-term STZ-induced diabetes mellitus, although the higher plasma lipid and cholesterol levels of the latter group may potentiate the degree of vascular damage.

Atrial structure and plasma ANF levels in rats with chronic diabetes mellitus.

The effect of streptozocin-induced diabetes (STZ-D) on right atrial structure was investigated in male Wistar rats. STZ (55 mg/kg) or saline (1 ml/kg) was administered by intravenous injection 12 wk before the experimental studies. Tissue was sampled from four regions of the atrium, processed, and embedded in plastic. Quantitative stereological analysis indicated that in STZ-D rats, there was a significant diminution in size of the musculi pectinati (muscular ridges), which form a network making up the wall of the atrium. In addition, within the muscular ridges, there was a significant reduction in the relative proportion of cardiocytes within the cardiac tissue. The rest of the cardiac tissue consisted of interstitial regions, connective tissue, and blood vessels, which correspondingly increased. This suggests there was some form of cardiomyopathy. When atrial granularity was determined relative to cardiocyte volume density, a significant decrease (54%) was found in tissue from STZ-D rats. The blood pressure of conscious STZ-D rats was significantly lower than control rats, whereas right atrial pressure was not different. The level of resting plasma immunoreactive atrial natriuretic factor (ANF) in conscious STZ-D rats (98 +/- 5 pg/ml) was significantly higher than in control rats (52 +/- 7 pg/ml). The decreased atrial granularity could be related to the higher resting plasma ANF levels, suggesting a more rapid turnover or increased synthesis bypassing storage in the granular form.

Relationship between atrial granularity and release of atrial natriuretic factor in rats with diabetes mellitus.

We examined the effect of a 25% blood volume expansion on the release of atrial natriuretic factor (ANF) in conscious Wistar rats (13-15 wk old) injected 6 wk earlier with streptozotocin (55 mg/kg iv, diabetic) or saline (1 ml/kg iv, control). The diabetic rats demonstrated a significant (P less than 0.05) resting hypotension (132 +/- 2/91 +/- 1 mmHg, systolic/diastolic) and bradycardia (340 +/- 5 beats/min) compared with the controls (145 +/- 2/98 +/- 2 mmHg, 377 +/- 8 beats/min). Resting plasma immunoreactive (IR) ANF levels were significantly (P less than 0.05) elevated in the diabetic rats (control: 72 +/- 4 pg/ml; diabetic: 87 +/- 4), although resting right atrial pressures were not different (control: 6.0 +/- 0.8 cmH2O; diabetic: 5.2 +/- 0.6). Volume expansion with donor blood from similarly treated animals significantly (P less than 0.05) elevated IR ANF levels in both groups, but the increase in the saline-injected group (+527 +/- 80 pg/ml) was significantly (P less than 0.05) greater than that of the streptozotocin-injected group (+323 +/- 45 pg/ml). Both groups showed similar elevations in right atrial pressure (control: +1.8 +/- 0.3 cmH2O; diabetic: +1.6 +/- 0.4). Morphological examination of tissue taken from right atria demonstrated no difference in cardiocyte volume percent per unit of tissue but a significant (P less than 0.05) reduction in the relative frequency of occurrence of atrial granules in the diabetic group. The cause of the reduction in atrial granularity in these animals is as yet unknown.

Blood pressure recovery following haemorrhage in rats with streptozotocin-induced diabetes mellitus.

The effect of hypotensive haemorrhage on blood pressure recovery was compared in saline- and streptozotocin-injected rats. Absolute plasma volumes (and calculated blood volumes) were not different between the two groups. After haemorrhage of similar volumes at similar rates, there were no significant differences in the recoveries in blood pressures or heart rates between control and diabetic animals. In other control and diabetic groups, posthaemorrhage treatment with the converting enzyme inhibitor captopril (at 20 min) and the vasopressin (V1-receptor) antagonist d(CH2)5DAVP (at 40 min) did not have any deleterious effects on blood pressure recovery at these times. These results support the proposition that neither the renin-angiotensin system nor vasopressin are importantly involved in blood pressure recovery at these time points after hypotensive haemorrhage in conscious rats. They are also consistent with the lack of difference between untreated control and diabetic groups, despite previous findings showing impairments of renin-angiotensin- and vasopressin-mediated effects after acute hypotension induced by pentolinium in diabetic rats.

Evidence for regionally selective changes in response to potassium chloride but not vasopressin or methoxamine in vasculature from diabetic rats.

In the present study we examined the contractile responses of aortae and mesenteric and femoral arteries taken from rats treated 3 weeks previously with streptozotocin (55 mg/kg, i.v.) or saline (1 mL/kg, i.v.) to vasopressin, potassium chloride, and methoxamine. The dose-response curves obtained with vasopressin and methoxamine were not significantly different between control and diabetic animals. However, both the diabetic mesenteric and femoral arteries showed a significantly (p less than 0.05) greater maximum response to potassium chloride as compared with their respective controls. The reactivity of the diabetic aortae to this agonist was not different. It is concluded that while the contractile responses of the diabetic tissues were normal when the agonist was vasopressin or methoxamine, there would appear to be regionally selective changes in responsiveness to potassium chloride.

Concentration(s) of atrial natriuretic hormone in the plasma of rats with streptozotocin-induced diabetes mellitus.

Blood was withdrawn from rats injected 1, 3, 6 and 12 weeks previously with the diabetogenic agent streptozotocin (55 mg/kg, I.V.) or saline. Analysis of plasma showed that while the streptozotocin-treated animals displayed significantly (p less than 0.05) diminished triiodothyronine levels and significantly (p less than 0.05) elevated osmolalities at all time points after injection, immunoreactive-ANF levels were unchanged. Thus, there would appear to be no direct relationship between plasma atrial natriuretic factor levels and plasma triiodothyronine levels or plasma osmolalities in the diabetic rat.

Pressor sensitivities to vasopressin, angiotensin II, or methoxamine in diabetic rats.

We investigated the pressor sensitivities to vasopressin, angiotensin II, and methoxamine of intact and ganglion-blocked rats that had been treated 21 days earlier with streptozotocin or saline. No differences in blood pressure or heart rate responses to vasopressin or angiotensin II were found between the intact groups when these peptides were administered intravenously in equimolar doses. After ganglion blockade a significant enhancement in pressor responsiveness to both vasopressin and angiotensin II was observed in the control groups, but in the streptozotocin-treated animals no enhancement in pressor sensitivity to vasopressin was found. Furthermore, although a significant augmentation of the responses to angiotensin II was observed, it was smaller than that seen in the ganglion-blocked control group. Neither group showed enhanced pressor responsiveness to methoxamine. These results indicate that the previously observed diminished contributions from endogenous vasopressin and the renin-angiotensin system to blood pressure recovery following ganglion blockade in streptozotocin-treated rats may have been due, at least in part, to diminished pressor responsiveness.

Abnormal blood pressure recovery during ganglion blockade in diabetic rats.

The aim of the present study was to determine the extent to which vasopressin or the renin-angiotensin system contributed to the recovery of blood pressure following acute hypotension induced by treatment with pentolinium and captopril, or pentolinium and the vasopressin antagonist d(CH2)5DAVP, respectively, in conscious, free-moving rats treated 21 days previously with saline or streptozotocin (STZ) (60 mg/kg ip). Half the animals given STZ were subsequently treated with insulin (about 4.5 U/day). The STZ-treated animals demonstrated a resting bradycardia and systolic hypotension. The vasopressin-mediated recovery in blood pressure seen following administration of pentolinium, in the presence of captopril, and the renin-angiotensin-mediated recovery seen following administration of pentolinium, in the presence of d(CH2)5DAVP, were both found to be significantly (P less than 0.05) attenuated in the STZ-treated animals. These abnormalities were absent in the animals injected with STZ and treated daily with insulin, but receiving their last dose 24 h before measurement. At that time the animals had elevated blood glucoses. These results indicate that the abnormalities observed were not due to toxic effects of STZ or to hyperglycemia per se.

The influence of streptozotocin-induced diabetes mellitus on fluid and electrolyte handling in rats.

Intakes and urine outputs of fluid and electrolytes were measured daily in rats before, and for 3 weeks after, induction of diabetes by intraperitoneal injection of streptozotocin (STZ; 60 mg/kg); control animals received saline. Water intakes and urine outputs were increased on and after the first day after injection with STZ; after a transient period of negative water balance, fluid intakes and urine outputs increased in parallel. Food intake was reduced for the first 3 days after injection of STZ but thereafter there was a steady increase. On the final experimental day, the food intake of the diabetic group was 60% greater than that of the control group. Urinary electrolyte excretion was increased after injection of STZ; at the end of the experiment, the increase in urinary sodium excretion was similar to the increase in intake but the increase in urinary potassium excretion was less. On day 21 after injection of STZ plasma sodium concentration and packed cell volume were significantly reduced in the diabetic group but plasma potassium concentration was not. There was a difference between the measured osmolality and the calculated osmolarity of the plasma of the diabetic animals which was not seen in the controls. This difference was not due to pseudohyponatraemia, but was probably due to the presence of unidentified solutes, since there was a significant gap between the urinary osmolal and osmolar excretion in the diabetic animals that was not present in the control animals.